Pigmentation Disorder

Clinics in Dermatology (2014) 32, 66–72

Pigmentation disorders: hyperpigmentationand hypopigmentationElectra Nicolaidou, MD, PhD, Andreas D. Katsambas, MD, PhD⁎

1st Department of Dermatology, University of Athens School of Medicine, “Andreas Sygros” Hospital,5 I. Dragoumi str, GR-16121, Athens, Greece

Abstract Pigmentation disorders include a large number of heterogeneous conditions that are usuallycharacterized by altered melanocyte density, melanin concentration, or both, and result in alteredpigmentation of the skin. Some of these disorders are extremely common (melasma, vitiligo), whereasothers are rare. In this contribution, we review the most common pigmentation disorders that appearon the face. These lesions, even though mostly asymptomatic, have a great impact on a patient’squality of life.© 2014 Elsevier Inc. All rights reserved.

Disorders of hyperpigmentation

Melasma

Melasma (a term derived from the Greek word melas,meaning black) is a common acquired hypermelanosis thatoccurs exclusively on sun-exposed areas, mostly on the faceand occasionally on the neck and forearms.

Epidemiology and etiologyMelasma is more common in women. Men have been

reported to represent 10% of cases.1 Melasma is moreapparent during and after periods of sun exposure.

The exact cause of melasma remains elusive, but the twomost important factors implicated in its etiopathogenesis aresunlight and genetic predisposition. Other factors incrimi-nated in the pathogenesis of melasma include pregnancy andexogenous hormones (ie, oral contraceptives and hormonereplacement therapy), thyroid dysfunction, cosmetics, andphototoxic and antiseizure drugs.2

⁎ Corresponding author. Tel.: +30 210 3619542; fax: +30 210 3600196.E-mail address: [email protected] (A.D. Katsambas).

0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clindermatol.2013.05.026

Clinical features and classificationThe number of hyperpigmented patches may range from

one single lesion to multiple patches located usuallysymmetrically on the face and occasionally the V-neck area.The lesions have serrated, irregular, and geographic borders(Figure 1). According to the distribution of lesions, thefollowing three clinical patterns of melasma are recognized2,3:

1. The centrofacial pattern. This is the most commonpattern. It involves the forehead, cheeks, upper lip,nose, and chin.

2. The malar pattern. This involves the cheeks and nose.3. The mandibular pattern. This involves the ramus of

the mandible.

Melasma can be classified into four histologic types usingWood’s light examination2,3:

1. Epidermal type. The pigmentation is intensified underWood’s light examination. It is the most common typeof melasma. Melanin is increased in all epidermallayers. Only a few scattered melanophages can beobserved in the papillary dermis.

2. Dermal type. The pigmentation is not increased underWood light examination. Many melanophages arethroughout the entire dermis.

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http://dx.doi.org/10.1016/j.clindermatol.2013.05.026

Fig. 1 Melasma of the forehead.

67Pigmentation disorders

3. Mixed type. Under Wood’s light examination, thepigmentation becomes more apparent only in someareas, whereas in others there is no change. Melanin isincreased in the epidermis, and there are many dermalmelanophages.

4. Indeterminate type. Wood’s light examination is of nobenefit in individuals with skin type VI.

In a recent study,4 however, Wood’s light examinationdid not accurately determine the depth of pigmentdeposition in patients with melasma. Dermal melanindeposition is common and it may be underestimated withWood’s light examination.

HistopathologyLight microscopic findings of melasma4,5 include in-

creased deposits of melanin in the epidermis or dermis, orboth, compared with adjacent normal skin and a mildperivascular lymphohistiocytic infiltrate. The number ofepidermal melanocytes in lesional skin has been assessed byimmunohistochemistry and has been reported to be bothincreased and similar to the number of melanocytes in normalskin. The melanocytes are enlarged, intensely stained, andwith very prominent dendrites. The number of dermalmelanophages in the dermis and their melanin deposition isincreased in the dermal and mixed type of the disease.Electron microscopy studies show increased melanosomes inboth melanocytes and keratinocytes in involved skin.

Treatment and prognosisSun protection is of pivotal importance in the treatment of

melasma. Without strict adherence, any treatment regimenwill fail. Recurrence during the summer is very common inpatients with melasma.

The treatment of melasma6 includes topical formula-tions, chemical peels, lasers, and light sources. Combina-tions of treatments are often used to maximize results indifficult cases.

Topical treatment with a combination of hydroquinone,tretinoin, and a steroid appears to be the most effectiveinitial therapy. Glycolic acid peels may be a usefuladjunct to topical treatment, especially after a patient’spretreatment with hydroquinone for 2 weeks to minimizethe risk for postprocedure hyperpigmentation. Fractionallaser therapy is the only laser treatment for melasma thathas been approved by the U.S. Food and DrugAdministration, and it could be used as a third-linetreatment in severe cases who have not responded toother treatments and who are willing to accept the riskfor postprocedure hyperpigmentation.

Pigmented contact dermatitis (Riehl melanosis)

Riehl melanosis is a pigmentary dermatosis character-ized by brownish gray facial pigmentation that is more

marked on the temples and the forehead. Today, Riehlmelanosis is almost synonymous with pigmented contactdermatitis, the most common cause of which are sensitizingchemicals in cosmetics.

Epidemiology and etiologyRiehl melanosis has mainly been reported in young and

middle-aged women.Riehl first described in 1917 a reticular black to brown-

violet pigmentation of the face and attributed it to exposureto “noxious substances.”7 The disease was common inVienna between 1916 and 1920. It was again frequentlyencountered in Europe during the Second World War, whenexposure to tar was thought to be responsible for theeruption, and in Japan, several decades later, where it wasfound to be due to allergic contact dermatitis from cosmetics.The causative allergens were coal tar dyes, particularlybrilliant lake red R and other 1-phenylazo-2-naphtholderivatives.8,9 Based on these findings, the terms pigmen-ted contact dermatitis and pigmented cosmetic dermatitishave been proposed for Riehl melanosis. The number of newcases since 1978 has declined, probably due to allergenavoidance in cosmetics. Reports of sporadic outbreaks andcases still continue. Chemicals that have been more recentlyimplicated with Riehl melanosis include geraniol in a facepowder,10 topical minoxidil 5%,11 and diphenylcycloprope-none.12 Ultraviolet (UV) irradiation may also play a role inthe pathogenesis of Riehl melanosis, through the induction ofphotocontact dermatitis.10

Clinical featuresThe pigmentary changes with Riehl melanosis occur

mainly on the face, but the neck, dorsal hands, and forearmscan also be affected. The patches usually have a reticularpattern and a black to brown-violet hue. Occasionally,erythematous macules or papules are present, suggesting amild contact dermatitis. Patch tests are used for theidentification of the offending substances.8–11

HistopathologyHistopathologic studies10 have shown liquefactive basal

cell degeneration, a dermal lymphohistiocytic infiltrate, athickened basal lamina, and a large number of melanophages

ig. 2 Erythema dyschromicum perstans. The patient had similarlesions on the face.

68 E. Nicolaidou, A.D. Katsambas

in the dermis. Spongiosis is absent. Direct immunofluores-cence studies are negative.

TreatmentRemoval of the causative agent, sun protection, and

topical treatment with hydroquinone usually improve theappearance of lesions.

Erythromelanosis follicularis faciei

Erythromelanosis follicularis faciei (EFF) is a rare diseasecharacterized by hyperpigmentation, erythema, and follicularpapules localized on the face and neck.

Epidemiology and etiologyEFFwas initially described in Asianmen and later in white

men.13 There are also a few reports of EFF in women.14 Thecause of the disorder is unknown. An autosomal recessivepattern of transmission has been reported in one family.15

Clinical featuresThe eruption usually begins as a red-brown telangiectatic

pigmentation in the preauricular regions that graduallyexpands and covers the cheeks in an irregular pattern. Palefollicular papules are present within the patches and there isloss of vellus hairs. Keratosis pilaris of the upper extremitiesand trunk is often observed in patients with EFF. Nophotosensitivity is reported by patients.

HistopathologyHyperkeratosis and dilatation of superficial dermal blood

vessels are observed in EFF lesions.16 Basal layer pigmen-tation reflects the clinical severity of hyperpigmentation.16

Enlargement of hair follicles from horny masses retained inthe infundibular region has also been reported.14

TreatmentApart from sun avoidance and topical hydroquinone, topical

keratolytics (10% urea, ammonium lactate 12%) can be usedfor the treatment of follicular papules. Laser treatment of thebackground erythema and hyperpigmentation can be tried.

Erythema dyschromicum perstans

Erythema dyschromicum perstans (EDP) or ashy derma-tosis is an idiopathic, acquired, and chronic skin disordercharacterized by hyperpigmented patches on the trunk, face,and extremities.

Epidemiology and etiologyMost adult patients with EPD are of Hispanic origin,17 but

white adult patients have also been reported. As far aschildren are concerned, there are more reports with whitechildren than with Hispanic children.18 There appears to beno sexual predilection for EDP.

The cause of EDP remains unknown. There is considerableevidence that an immunologic mechanism is involved in the

pathogenesis of the disease.19 A variety of possible causativeagents have been reported,17,18 including ingestion ofammonium nitrate, orally administered X-ray contrast media,exposure to chlorothalonil, chronic hepatitis C infection, andexposure to environmental contaminants.

Clinical featuresEDP is characterized by oval or round-shaped blue-gray

patches over the face, trunk, and extremities (Figure 2). Earlylesions may have a raised, erythematous border thatdisappears later, and usually it is not evident upon initialconsultation. The lesions are occasionally pruritic, and theirdiameter may vary from a few millimeters to severalcentimeters. The trunk and proximal extremities are moreusually affected, followed by the face and neck. There seemsto be no predilection for exposed or unexposed areas.

HistopathologyThe histologic features of EDP are relatively nonspeci-

fic.18 The inflammatory border of the lesions may showvacuolization of the basal cell layer and occasional colloidbodies. There is also mononuclear infiltrate of the mid andupper dermis, and pigment incontinence with many melano-phages. In the inactive lesions, the incontinence of pigmentprevails, whereas the vacuolization of the basal cell layer andthe cellular infiltrate show different degrees of intensity.

TreatmentThere is no consistently effective therapy for EDP. In

children, a high rate of spontaneous remission has beenobserved.18 Dapsone, clofazimine, and narrow-band UVBphototherapy have been used with good results in smallseries.19,20

Poikiloderma of Civatte

Poikiloderma is a combination of linear telangiectasia,mottled hyperpigmentation/depigmentation, and superficial

F

image of Fig.�2

ig. 3 Poikiloderma of Civatte. (Courtesy of Alexander C.atoulis, MD, Athens, Greece.)


atrophy in a reticular pattern. Poikiloderma of Civatte (PC) isa rather common, benign, acquired poikiloderma of the faceand neck.

Epidemiology and etiology

PC occurs most frequently in fair-skinned, middle-aged,or elderly women; however, the disease has been seen inother age groups, as well as in men.21

The cause of PC remains obscure. The predilection forsun-exposed areas suggests a fundamental role for chronicsun exposure. Hormonal factors in combination with thenormal aging process may also be involved, as is suggestedby the age and sex distribution of the patients.

Photosensitizing chemicals in perfumes or cosmeticshave been implicated in the pathogenesis of the disorder,and a statistically significant difference of positive patchtest reactions to fragrances has been reported in patientswith PC compared with control subjects.22 Geneticpredisposition, possibly expressed as an increased suscep-tibility to sun radiation, has also been implicated in thepathogenesis of the disorder.23

Clinical featuresSymmetrical patches with reddish brown, reticulate

pigmentation, telangiectasia, and atrophy develop on thelateral cheeks and the sides of the neck (Figure 3). Thearea shaded by the chin is not affected. Lesions usuallyare asymptomatic, but occasionally patients report rosa-cealike flushing.21 PC runs a chronic, benign, butirreversible course.

HistopathologyThe epidermis is atrophic and there is hydropic

degeneration of the basal layer. Numerous melanophagesare present in the dermis along with a perivascular orbandlike lymphocytic infiltrate. In late stages, dilated bloodvessels are demonstrated.

TreatmentPulse dye laser and ablative fractional laser resurfacing

have been used with variable results.24

Phototoxic dermatitis

Phototoxic dermatitis is initiated by a photochemicalreaction between UV radiation and a phototoxic substance.Phototoxic substances can be applied topically (psoralens),ingested (several drugs), or contacted accidentally (photo-toxic plants). After exposure to the sun, erythema and blistersusually develop. Prominent postinflammatory hyperpigmen-tation is a typical characteristic.

Berloque dermatitis is the result of the topical applicationof the phototoxic oil of bergamot or related substancesfound in perfumes and other cosmetics. If sun exposure is

FK

minimal, then hyperpigmentation of the face and neck,usually in a streaked pattern, may appear with little or noerythema. Histopathology shows increased melanin in thebasal layer and, in later stages, accumulation of melanin indermal melanophages.

Drug-induced facial hyperpigmentationNumerous medications have been implicated in the

appearance of dark lesions on the skin. Drugs can causehyperproduction of melanin by stimulating epidermalmelanocytes, either directly or indirectly, through anonspecific cutaneous inflammation. They may alsoimpair melanin clearance from dermal macrophages bybinding to melanin and creating a stable complex. Theaccumulated melanin is found either free in the dermis orwithin dermal macrophages. Apart from the accumulationof melanin, other mechanisms responsible for drug-induced dark lesions include the accumulation of thetriggering medication itself, the synthesis of specialpigments under the influence of the drug, and thedeposition of iron from drug-induced damage to dermalvessels.25 More than one of the above mechanisms aresometimes implicated in a drug-induced lesion, and todistinguish these lesions from true hypermelanosis, we usefor them the term hyperpigmentation.

Drugs that can cause hyperpigmentation of the faceinclude antimalarials, amiodarone, cytotoxic drugs, minocy-cline, phenothiazines (mainly chlorpromazine), tricyclicantidepressants (particularly imipramine and desipramine),and anticonvulsants.

Drug-induced hyperpigmentation usually has a slowonset and progresses very gradually over months or evenyears after the initiation of the drug. Apart from the usualbrownish coloration that we observe in most facialhypermelanoses, drug-induced hyperpigmentation mayalso have a blue-gray hue (Figure 4). Sun-exposedareas, as well as mucous membranes (mouth, conjuncti-vae), are favorite sites for the lesions, and sun exposureusually aggravates them. Other lesions, such as

image of Fig.�3


inflammatory or lichenoid rashes, may accompany thedrug-induced hyperpigmentation, which usually fades,although not always completely, when the responsiblemedication is discontinued.

Histologic findings of drug-induced hyperpigmentationare quite variable and depend on the causative factor.Usually, melanin, another pigment, or both can be foundeither free in the dermis or within dermal macrophages.

Facial hypermelanosis secondary tosystemic disorders

Addison diseaseAddison disease is caused by a primary adrenocortical

insufficiency. It is characterized by hypermelanosis, weak-ness, nausea, vomiting, and diarrhea. Laboratory findingsinclude low serum sodium level, high serum potassium level,and elevated blood urea nitrogen. The diagnosis is confirmedby specific tests for adrenal insufficiency.

The hypermelanosis in Addison disease occurs as achange in the intensity of normal skin pigmentation or as thedevelopment of new areas of pigmentation, for example,gingival or buccal mucous membrane. It results from themelanogenic action of increased blood levels of certainpituitary peptides. There is increased melanin in melanocytesand there may be melanophages in the dermis.

HemochromatosisIn hemochromatosis, one of the most common genetic

disorders, iron is deposited in a variety of tissues, leading to awhole spectrum of systemic findings. Serum ferritin andserum iron are elevated.

The skin acquires a slate gray or gray-brown discolor-ation. Light exposed areas, such as the face and the back ofthe hands, are more prominently involved. Other cutaneoussigns include ichthyosislike changes, alopecia, koilonychia,and spotty intraoral pigmentation.

Histopathologically, there is increased basal layer mela-nin and deposition of hemosiderin in the dermis. Sometimes,

Fig. 4 Drug-induced hyperpigmentation. The patient had similarlesions on the body.

the pigment is concentrated around sweat glands andendothelial cells.

Porphyria cutanea tardaMany patients with porphyria cutanea tarda have facial

hyperpigmentation resembling melasma. Other associatedfeatures include bullae, atrophic scars, milia, and facialhirsutism. There is a massive increase in all urine porphyrins.

Disorders of hypopigmentation

Vitiligo

Vitiligo is an acquired disease characterized by destruc-tion of functional melanocytes mainly in the skin, resultingin the appearance of well-circumscribed white maculesand patches.

Epidemiology and etiologyVitiligo is a common disease, affecting 0.5% to 2% of the

general population. Age of onset during childhood has beenreported in 25% to 30% of patients.26 There is no clear sexpredilection for the disease.

Vitiligo is a multifactorial disease related to both geneticand environmental factors.27 The absence of functionalmelanocytes in vitiligo skin is probably the result of theirdestruction.

Several pathogenic hypotheses for the destruction ofmelanocytes have been proposed:

• The autoimmune hypothesis• The intrinsic defect of melanocytes hypothesis• The defective free radical defense hypothesis• The reduced melanocyte survival hypothesis• The transepidermal melanocytorrhagy hypothesis

It is possible that vitiligo is not a single disorder but rathera common phenotype of several different pathophysiologi-cally disorders.

Clinical features and classificationVitiligo is characterized by milk-white macules and

patches with discrete margins. Lesions are usually symmet-rically distributed on the face (Figure 5), neck, axillae,elbows, knees, shins, and dorsal aspect of the hands and feet.

The following classification divides vitiligo into threegeneral types: localized, generalized, and universal.

1. Localizeda. Focal: one or more lesions in one area, but not in

a segmental distributionb. Segmental: one or more lesions involving a

unilateral segment of the body2. Generalized

image of Fig.�4

Fig. 5 Vitiligo on the face.


a. Vulgaris: scattered lesions widely distributed, uni-versal (more than 80% of body surface area affected)

b. Acrofacial: several lesions on the extremities andface

3. Universal: more than 80% of body surface areaaffected

HistopathologyIn classical vitiligo, no dihydroxyphenylalanine-positive

melanocytes can be detected. In early lesions, some melano-cytes with decreased dihydroxyphenylalanine-positivity canbe detected.

Treatment and prognosisThe course of vitiligo is unpredictable. The disease may

stabilize for a long period or exacerbate rapidly. Spontaneousrepigmentation has also been reported, especially in thesummer. Some patients report development of new lesions instressful periods.

Several treatment modalities have been used for themanagement of vitiligo.28–31 Topical corticosteroids, topicalcalcineurin inhibitors (tacrolimus and pimecrolimus), pho-totherapy (narrowband UVB, photochemotherapy), excimerlaser, and surgery (minigrafting, suction blister epidermalgrafting, grafting of cultured autologous melanocytes, andgrafting of non-cultured epidermal cell suspensions) have allbeen used with variable results. Lesions on the face andpatients with darker skin phototype (III-V) respond better totreatment. In widespread disease, depigmentation of islandsof normally pigmented skin with 20% monobenzyl ether ofhydroquinone is an option.

Psychological support can be helpful to many patients, asit is a caring and sympathetic approach by the dermatologist.

Postinflammatory hypomelanosis

Cutaneous inflammation can alter several pathways thatregulate skin color, resulting in the appearance of residualhypopigmented lesions. Many dermatoses, including psori-asis, seborrheic dermatitis, atopic dermatitis, sarcoidosis,mycoses fungoides, and lupus can lead to postinflammatoryhypopigmentation.

Lesions of postinflammatory hypopigmentation usuallygradually resolve. In resistant cases, UVB phototherapy andepidermal or melanocyte grafting may be helpful.

Pityriasis albaPityriasis alba is a very common condition that is formally

categorized as postinflammatory hypomelanosis, eventhough its actual pathogenesis is not completely clear. It ischaracterized by multiple ill-defined macules and patchesthat are symmetrically distributed mainly on the face,particularly the cheeks. The lesions are hypopigmentedwith pityriasiform scaling and may persist for months oryears before resolving spontaneously. Histologically, there issubacute spongiotic dermatitis with decreased melanin in theepidermis. No treatment is more effective than emollients.

Piebaldism

Piebaldism is an autosomal dominant disorder charac-terized by poliosis and stable, circumscribed areas ofleukoderma.

Epidemiology and etiologyPiebaldism is quite uncommon. It is estimated to occur in

1 to 40,000 white individuals. It results from mutations in theKIT proto-oncogene, which encodes a member of thetyrosinase kinase family of transmembrane receptors that isfound on the surface of melanocytes.32 The KIT receptor isrequired for the normal development of melanocytes.

Clinical featuresThe lesions are present at birth. Scalp poliosis (white

forelock) is present in 80% to 90% of patients. All the hairsof the forelock are white, and the underlying skin is alsoamelanotic. This white patch is midline in location and canextend up to the root of the nose. Poliosis of the eyebrowsand eyelashes is common.

Apart from the face, amelanotic lesions appear also on thetrunk and extremities. They are irregular in shape, well-circumscribed, and contain normally pigmented and hyper-pigmented macules and patches. The presence of lesionssince birth, the stability of lesions, and the presence ofpigmented patches within lesions differentiate piebaldismfrom vitiligo.

image of Fig.�5


HistopathologyNo melanocytes can be found in either the epidermis or

the hair follicles of lesional skin. Melanocytes andkeratinocytes of hyperpigmented macules have an abun-dance of melanosomes.

Treatment and prognosisLesions are stable. Surgical treatment with autologous

transplantation techniques (minigrafting, suction blisterepidermal grafting, grafting of cultured autologous melano-cytes, and grafting of noncultured epidermal cell suspen-sions) can be used to improve the appearance of lesions.

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Pigmentation Disorder