Disorders of Hyperpigmentation




Abstract


Disorders of hyperpigmentation usually result from an increase in melanin production, which is occasionally associated with an increased density of active melanocytes. Skin discoloration may also be caused by dermal deposition of exogenous substances such as drugs or heavy metals. Clinically, disorders of hyperpigmentation can be classified into diffuse, circumscribed, linear, and reticulated subsets. This chapter reviews disorders within each of these categories, including both common and rare conditions. A discussion of dyschromatoses, disorders characterized by both hypo- and hyperpigmentation, follows.




Keywords

diffuse hyperpigmentation, flagellate pigmentation, reticulated hyperpigmentation, linear hyperpigmentation, postinflammatory hyperpigmentation, dyschromatosis, melasma, erythema dyschromicum perstans, pigmentary demarcation lines, pigmentary mosaicism, flagellate pigmentation, prurigo pigmentosa, dyskeratosis congenital, Naegeli–Franceschetti–Jadassohn syndrome, dermatopathia pigmentosa reticularis, X-linked reticulate pigmentary disorder, Dowling–Degos disease, reticulate acropigmentation of Kitamura, dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria

 


Skin color depends upon the amount and distribution of melanin and other pigments such as hemoglobin, which can influence light absorption, reflection, and scattering. Disorders of hyperpigmentation usually result from an increase in melanin production and, on occasion, from an increase in the density of active melanocytes. Discoloration of the skin may also be caused by deposition of exogenous substances such as drugs, drug complexes (e.g. with melanin or iron), or heavy metals within the dermis.


To aid in the clinical approach, disorders of hyperpigmentation can be divided into diffuse, circumscribed, linear, and reticulated subsets ( Fig. 67.1 ). A discussion of each of these categories is followed by an overview of dyschromatoses, disorders characterized by both hypo- and hyperpigmentation. Benign melanocytic neoplasms are covered in Chapter 112 .




Fig. 67.1


Approach to disorders of hyperpigmentation .




Diffuse and Circumscribed Hyperpigmentation


Introduction


Diffuse and circumscribed hyperpigmentation are discussed together because both postinflammatory hyperpigmentation (PIH) and reactions to systemic drugs, two major causes of hyperpigmentation, can assume either of these patterns. PIH most often presents as circumscribed lesions, and the size, shape, and distribution pattern provide clues to the etiology. Melasma is another common cause of circumscribed hypermelanosis. Diffuse hyperpigmentation can also be a manifestation of metabolic diseases, sclerodermoid disorders, nutritional deficiencies, and occasionally HIV infection.


Postinflammatory Hyperpigmentation




Synonym


▪ Postinflammatory hypermelanosis



Key features





  • Extremely common, especially in individuals with more darkly pigmented skin



  • Develops after inflammation or injury to the skin, but preceding inflammation may be transient or subclinical



  • The increased melanin may be primarily within the dermis (e.g. following lichen planus) or in the epidermis (e.g. following acne or atopic dermatitis)



  • Epidermal hyperpigmentation fades more readily than dermal hyperpigmentation




Introduction


PIH represents an acquired excess of melanin pigment following cutaneous inflammation or injury. It can occur anywhere on the skin surface, including the mucous membranes and the nail unit. PIH is extremely common and can have significant cosmetic and psychosocial consequences.


Epidemiology


PIH can occur at any age and there is no gender preference. Individuals with darkly pigmented skin tend to have a greater frequency, severity, and duration of PIH than those with lighter complexions.


Pathogenesis


In the epidermal form of PIH, there is increased melanin production and/or transfer to keratinocytes. Inflammatory mediators (e.g. prostaglandins E 2 and D 2 ) that enhance pigment production may play a role in this process. In dermal hyperpigmentation, melanin enters (“falls into”) the dermis via a damaged basement membrane, where it is phagocytosed by and subsequently resides within dermal macrophages (referred to as melanophages). Macrophages may also migrate into the epidermis, phagocytose melanosomes, and then return to the dermis. Melanin within dermal melanophages tends to persist for long periods of time (e.g. years).


Clinical Features


Asymptomatic hyperpigmented macules and patches range in color either from tan to dark brown (epidermal melanin) or from gray–blue to gray–brown (dermal melanin). Primary lesions of the underlying inflammatory disorder may or may not be evident admixed with the hyperpigmentation or elsewhere. When primary lesions are absent, the size, shape, and distribution pattern of the hyperpigmented lesions may provide clues to the underlying etiology ( Table 67.1 ). PIH can be exa­cerbated by continued inflammation, trauma, exposure to ultraviolet (UV) irradiation, or treatment-related irritation.



Table 67.1

Disorders associated with postinflammatory hyperpigmentation.

Adapted from Bolognia JL. Disorders of hypopigmentation and hyperpigmentation. In: Harper J, Oranje A, Prose N (eds). Textbook of Pediatric Dermatology, 2nd edn. Oxford: Blackwell Science, 2006:997–1040.















































































DISORDERS ASSOCIATED WITH POSTINFLAMMATORY HYPERPIGMENTATION
Inflammatory disease Clinical clues
Common
Acne vulgaris Head/neck region, upper trunk; <1 cm; perifollicular
Atopic dermatitis Atopic diathesis; face and extensor extremities in infants, then later flexural involvement; excoriations; atopic pleats; xerosis; lichenification; transverse nasal crease (“allergic salute”)
Impetigo Favors face; most common in children
Insect bites Favor exposed areas; usually <1 cm; lower extremities common with flea bites; clustered and sometimes linear patterns (“breakfast–lunch–dinner”; see Fig. 67.2B )
Lichen simplex chronicus Common locations: posterior neck, ankle, scrotum
Transient neonatal pustular melanosis Black newborns; pustules precede pigmentation (see Fig. 67.2C )
Less common
Irritant and allergic contact and photocontact dermatitis Sites determined by etiologic agent and form of exposure; phytophotodermatitis associated with linear hyperpigmentation in sun-exposed areas
Pityriasis rosea Favors trunk and proximal extremities; lesions follow skin cleavage lines; oval-shaped
Psoriasis Scalp/nail involvement; knees/elbows most common sites (see Fig. 67.2D )
Seborrheic dermatitis Favors face (especially forehead, upper eyelids, nasolabial folds, mental fold), skin folds, and presternal area; scalp/ear involvement; may also have hypopigmentation
Polymorphous light eruption Extensor upper extremities, mid upper chest, face; seasonal (e.g. spring or early summer)
Discoid lupus erythematosus Face and conchal bowls, with follicular plugging in latter site; oral lesions; in scarred lesions, central hypopigmentation with rim of hyperpigmentation
Lichen planus Wrists, shins, presacral; nail/oral involvement
Erythema dyschromicum perstans (EDP; ashy dermatosis) * Neck, proximal upper extremities, trunk; round or oval in shape with gray–brown to blue–gray color; long axis can follow skin cleavage lines (similar to pityriasis rosea); less commonly observed in fair-skinned individuals
Idiopathic eruptive macular pigmentation * Trunk, proximal extremities, neck, face; round or oval, discrete brown macules and small patches; sometimes barely elevated plaques with a subtle velvety texture; histologically, basal epidermal hyperpigmentation ± papillomatosis, with no vacuolar alteration and relatively few dermal melanophages compared to EDP; affects primarily children and adolescents, lasting months to years
Fixed drug eruption Circular; favors perioral, acral and genital sites; recurrence at same site(s) with repeated exposure (see Fig. 67.2E )
Morbilliform drug eruption Widespread; usually discrete lesions, history of drug exposure
Viral exanthem Widespread; usually discrete lesions; history of associated symptoms
Morphea Trunk or extremities; large-sized except in guttate variant; may be linear; associated induration and later dermal atrophy
Atrophoderma of Pasini and Pierini Trunk; large-sized; depressed with “cliff sign” at periphery no induration
Neurotic (psychogenic) excoriation, acne excoriée Favors face, scalp, extensor surface of arms, upper back (reachable areas); linear or angular shapes; multiple stages of evolution, from erosions/ulcerations to scars
Flagellate erythema Associated with bleomycin use, shiitake mushroom ingestion, dermatomyositis, and Still disease

* Typically no preceding inflammatory phase evident clinically or histologically.



Disorders that commonly lead to epidermal PIH include acne, insect bites, pyodermas, atopic dermatitis, psoriasis, and pityriasis rosea ( Fig. 67.2A–D ). In contrast, dermal PIH is associated with dermatoses characterized by degeneration of the basal layer of the epidermis and inflammation at the dermal–epidermal junction, such as lichen planus, lichenoid drug reactions, lupus erythematosus, and fixed drug eruptions ( Fig. 67.2E ). Upon treatment of the underlying disorder, epidermal PIH generally resolves over time, although fading may require months or years in darkly pigmented individuals. Dermal melanosis tends to persist longer and is sometimes permanent.




Fig. 67.2


Postinflammatory hyperpigmentation (PIH).

The lesions were caused by pemphigus foliaceus ( A ), insect bite reactions ( B ), transient neonatal pustular melanosis ( C ), a fixed drug eruption induced by trimethoprim-sulfamethoxazole ( D ), and psoriasis ( E ). Note the residual inflammation and “breakfast–lunch–dinner” configuration in B.

A–C, Courtesy, Julie V Schaffer, MD; D,E Courtesy, Justin Finch, MD.


Pathology


Epidermal PIH is characterized by increased pigment in keratinocytes and dermal PIH by melanophages within the dermis.


Differential Diagnosis


The size, shape, and distribution of the hyperpigmented lesions can provide clues to the inflammatory disease or injury that preceded PIH (see Table 67.1 ), and a thorough skin examination may detect active primary lesions. A history of prior inflammatory lesions and medication use (including prescription, over-the-counter, and alternative products) should be obtained. Disorders such as erythema dyschromicum perstans, melasma, pityriasis versicolor, and atrophoderma of Pasini and Pierini should be considered in patients without evidence of preceding inflammation by history or on examination. Occasionally, a biopsy may assist in establishing the diagnosis.


Treatment


Provided that the underlying dermatosis is successfully treated, PIH eventually improves in most patients, especially those with epidermal hypermelanosis. Sun protection, including daily application of a broad-spectrum sunscreen, can help to prevent accentuation of the pigmentation by UV exposure. Topical hydroquinone (2–4%) may lead to lightening over 3–6 months if the increase in pigmentation is limited to the epidermis. As with melasma (see below), use of a topical retinoid and corticosteroid together with hydroquinone may be more effective than monotherapy. Topical azelaic acid, α-hydroxy acid, L-ascorbic acid, and kojic acid as well as arbutin, licorice extracts, mequinol, niacinamide, N -acetyl glucosamine, and soy are additional potential therapeutic options . However, it is important to avoid irritant contact dermatitis from any topical agent. Chemical peels (e.g. with salicylic or glycolic acid) and laser therapy may be of benefit but can also result in hypopigmentation, especially in patients with darkly pigmented skin. Q-switched ruby, alexandrite, and Nd:YAG lasers are variably successful in removing dermal pigment (see Ch. 137 ).


Erythema Dyschromicum Perstans




Synonyms


▪ Ashy dermatosis ▪ Dermatosis cenicienta



Key features





  • Most common in individuals with skin phototypes III–IV



  • Gray–brown to blue–gray macules and patches in a symmetric distribution



  • Favors the neck, trunk, and proximal extremities



  • A consistently effective treatment is not currently available




Introduction


Ramirez first described erythema dyschromicum perstans (EDP) in 1957, referring to affected individuals as los cenicientos (ashen ones). This is an asymptomatic, slowly progressive eruption that is characterized by circumscribed areas of dermal pigmentation .


Epidemiology


Although EDP occurs worldwide, it is most common in Latin America. There is no gender preference. The disorder usually presents during the second to third decade, but it occasionally develops in younger children or older adults.


Pathogenesis


The etiology of EDP is not known. Although it has been postulated that a cell-mediated immune reaction to an ingestant, contactant, or microorganism underlies the discrete areas of pigmentary incontinence, no causal agent has consistently been identified . In most patients, a trigger is never found. However, there have been reports of EDP developing in association with the ingestion of ammonium nitrate, oral X-ray contrast media, and medications (e.g. benzodiazepines, penicillin); exposure to various pesticides, fungicides or toxins; endocrinopathies such as thyroid disease; and whipworm and HIV infections. The presence of the HLA-DR4 allele may represent a risk factor for EDP in Mexican patients.


Clinical Features


Oval, circular, or irregularly shaped macules and patches that are 0.5 to 3 cm in diameter and slate-gray to blue–brown in color develop gradually in a symmetric pattern and may coalesce ( Fig. 67.3A ). The initial site of involvement is often the trunk, with subsequent spread to the neck, proximal upper extremities, and sometimes the face. The mucous membranes are spared, and the palms, soles, and scalp are rarely affected. Occasionally, early lesions have a thin, raised, erythematous border, which tends to resolve over a few months, and the long axis of lesions may follow skin cleavage lines. Peripheral hypopigmentation may be seen in older lesions.




Fig. 67.3


Erythema dyschromicum perstans (ashy dermatosis).

A Multiple gray–brown macules and patches on the abdomen; note the coalescence of lesions. The “ashy” color is characteristic. B Histopathologic features include vacuolar degeneration of the basal layer, a sparse perivascular lymphocytic infiltrate, and prominent dermal melanophages (see inset).

B, Courtesy, Lorenzo Cerroni, MD.


EDP is usually asymptomatic but can be mildly pruritic. The disease progresses slowly and typically does not regress in adults. However, in one study of 33 prepubertal children, the majority of whom were Caucasian, the disease spontaneously resolved in two-thirds of the patients, with no recurrences over the ensuing 2–3 years .


Pathology


In early (“active”) lesions, vacuolar degeneration of the basal cell layer, a perivascular mononuclear cell infiltrate and melanophages in the upper dermis, and increased epidermal melanin are seen ( Fig. 67.3B ). Colloid bodies and dermal hemosiderin may be present. Immunohistochemical findings include expression of cell adhesion and lymphocyte activation molecules (e.g. CD36, intercellular adhesion molecule-1 [ICAM-1], CD69, CD94) that are associated with inflammation and activation of cytotoxic T cells. In later (“inactive”) lesions, the number of melanophages in the superficial dermis is increased but hydropic changes within the basal cell layer are absent and the dermal mononuclear cell infiltrate is minimal or absent.


Differential Diagnosis


Idiopathic eruptive macular hyperpigmentation (IEMH) features brown macules and patches with a similar size and distribution as in EDP but primarily epidermal pigment; recent studies have emphasized a velvety surface and papillomatosis histologically (see Table 67.1 ). The differential diagnosis of EDP also includes a lichenoid drug eruption (see Ch. 11 ), lichen planus (especially lichen planus pigmentosus), generalized fixed drug eruption, mastocytosis, and (less often) infectious diseases such as leprosy or pinta.


Treatment


There is no consistently effective therapy for EDP. Topical corticosteroids and hydroquinone are generally of no benefit. Topical tacrolimus and oral corticosteroids, antibiotics, antimalarials, isoniazid, and griseofulvin, as well as UV light therapy, have produced variable results. Successful treatment with dapsone and clofazimine has been reported in small series.


Lichen Planus Pigmentosus




Key features





  • Variant of lichen planus most commonly described in adults with skin phototypes III–V



  • Gray–brown to dark brown macules and patches either in a photodistribution or in an inverse (intertriginous) pattern


Lichen planus pigmentosus (LPP) is an uncommon variant of lichen planus that favors young to middle-aged adults with skin phototypes III–V, including those from India , Latin America, and the Middle East. It presents as irregularly shaped or oval, brown to gray–brown macules and patches in either sun-exposed areas (especially the forehead, temples and neck) or intertriginous zones ( Fig. 67.4 ). It is usually asymptomatic, but some patients describe mild pruritus or burning. In contrast to EDP, early lesions with an erythematous border are not a feature of LPP. While the distribution is symmetric in the vast majority of patients, a unilateral linear variant has also been described. Occasionally, a reticulated or follicular pattern is observed. The palms, soles, nails, and oral mucosa are usually not involved. In one series of 124 patients with LPP, 19 were noted to also have typical lesions of lichen planus . LPP is a chronic disorder with exacerbations and remissions. Histologic findings include a flattened epidermis with basal cell degeneration, and a variably dense band-like or perivascular infiltrate in the upper dermis admixed with melanophages.


Fig. 67.4


Lichen planus pigmentosus.

Multiple coalescing brown to gray–brown macules in the axilla of a middle-aged woman.


The etiology of LPP is unknown. The photodistribution in some patients suggests that UV can play a pathogenic role, and topical application of mustard oil (which contains allyl isothiocyanate, a potential photosensitizer) and amla oil have been proposed as possible inciting agents . The differential diagnosis includes the actinic and inverse variants of lichen planus (see Ch. 11 ), a lichenoid drug eruption, EDP, melasma and the entities listed in Table 67.2 when facial, PIH, and cutaneous T-cell lymphoma. In one uncontrolled study, lightening of the pigmentation occurred in 54% (7/13) of patients treated with topical tacrolimus for 12–16 weeks .



Table 67.2

Differential diagnosis of melasma.













































DIFFERENTIAL DIAGNOSIS OF MELASMA
Disorder Key differences from melasma/comments
Drug-induced hyperpigmentation or discoloration


  • History of medication use (e.g. doxycycline, amiodarone; see Table 67.4 )



  • Hyperpigmentation less patterned and less irregular in outline; may involve tip of nose



  • Discrete oval or round shape of fixed drug eruption rarely confused with melasma



  • May follow phototoxic drug reaction



  • Oral contraceptives and phenytoin may exacerbate melasma

Postinflammatory hyperpigmentation, e.g. due to cutaneous lupus erythematosus, photosensitivity reactions, contact dermatitis (e.g. irritant contact dermatitis to hydroquinone or tretinoin), or other forms of dermatitis


  • History of inflammatory phase with erythema, scale, and possible pruritus or burning



  • Primary lesions – may be admixed or elsewhere on body

Pigmented contact dermatitis (Riehl melanosis)


  • Favors sites of application of contactants, especially cosmetics



  • May be reticulated



  • Brown–grey color due to dermal melanin deposits



  • Histologic features: vacuolar degeneration of basal layer and lichenoid infiltrate in early lesions

Acquired bilateral nevus of Ota-like macules (Hori nevus)


  • Asian women, usually during the fourth or fifth decade of life



  • Multiple brown–gray to brown–blue macules, primarily in the malar region



  • Less common sites: lateral forehead, temples, upper eyelids, nasal root or alae



  • Lack of ocular or mucosal involvement



  • Histologic features: pigment-producing dermal melanocytes

Actinic lichen planus


  • Fine scale overlying violaceous lesions if inflammatory phase still present



  • Histologic features: hydropic degeneration of basal layer, lichenoid infiltrate

Lichen planus pigmentosus


  • Often begins on the temples/in the preauricular area and involves the neck



  • Coexistent classic lichen planus (~20% of patients)



  • Histologic features: vacuolar degeneration of basal layer; variable lichenoid infiltrate and epidermal atrophy

Erythema dyschromicum perstans


  • Inflammatory phase with rim of erythema occasionally seen



  • Lesions slate-gray to blue–brown



  • Distribution includes sun-protected areas

Exogenous ochronosis


  • History of hydroquinone application to areas of hyperpigmentation followed by progressive darkening



  • Superimposed small pigmented papules may also be seen



  • Histologic features: banana-shaped, yellow–brown deposits in the dermis (see Fig. 67.8 )

Cutaneous mercury deposits


  • History of use of mercury-containing soaps or creams



  • Dermatitis often present



  • Histologic features: brown–black granules free in dermis, in association with elastic fibers and within macrophages

Erythromelanosis follicularis faciei et colli


  • Red–brown patches on lateral cheeks and neck



  • Superimposed tiny pale follicular papules

Poikiloderma of Civatte


  • Presence of atrophy and telangiectasias



  • Favors lateral and inferior aspects of anterior neck; sparing of perifollicular skin and submental region

Acanthosis nigricans


  • Velvety plaques in the hollow of the cheek and preauricular



Melasma




Synonyms


▪ Chloasma ▪ Mask of pregnancy



Key features





  • At least 90% of patients are women



  • Increased prevalence in individuals who are Hispanic, or of Asian or African descent



  • Most common location is the face, followed by the forearms



  • Symmetric patches of hyperpigmentation with irregular borders due to increased melanin within the epidermis and/or dermis




Introduction and Epidemiology


Melasma is a common acquired disorder characterized by symmetric, hyperpigmented patches with an irregular outline, occurring most commonly on the face. It is most prevalent among young to middle-aged women who are Hispanic or of Asian, African, or Middle Eastern descent. Exacerbating factors include sun exposure, pregnancy, and use of oral contraceptives.


Pathogenesis


Although the exact pathogenesis of melasma is unknown, it is hypothesized that following exposure to UV irradiation or another inducer, hyperfunctional melanocytes within involved skin produce increased amounts of melanin . The key role of UV irradiation is supported by fading of lesions during winter months and a distribution pattern characterized by involvement of sun-exposed regions and sparing of relatively sun-protected sites such as the philtrum. In addition to oral contraceptive use and hyperestrogenic states, other medications (e.g. phenytoin, phototoxic drugs) and disorders (e.g. autoimmune thyroid disease) have the potential to aggravate melasma. Increased expression of KIT and stem cell factor within the lesional epidermis and dermis, respectively, may play a role in the hyperpigmentation of melasma .


Clinical Features


Light to dark brown or brown–gray patches with irregular borders appear primarily on the face ( Fig. 67.5 ). The areas of hypermelanosis are distributed symmetrically in three classic patterns: (1) centrofacial (most common), involving the forehead, cheeks, nose, upper lip (sparing the philtrum and nasolabial folds), and chin; (2) malar , affecting the cheeks and nose; and (3) mandibular , along the jawline. Less common sites include the extensor aspect of the forearms and mid upper chest. Lesions often first appear or are accentuated following exposure to UV irradiation or during pregnancy. In lightly pigmented individuals, this “mask of pregnancy” frequently diminishes or disappears after parturition, but it tends to persist in women with more darkly pigmented skin.




Fig. 67.5


Various forms of melasma and melasma-like hyperpigmentation.

A Malar variant. B Mild centrofacial type with sparing of the philtrum. C Extension of the hyperpigmentation onto the mandible. D Involvement of the extensor forearm; note the same irregular outline as is seen on the face. E Melasma-like appearance in a patient with previous acute cutaneous lupus erythematosus.

C–E, Courtesy, Jean L Bolognia, MD.


Melasma has classically been subdivided into four types based upon the primary location of the pigment: epidermal, dermal, mixed, or indeterminate (e.g. in patients with very dark skin pigmentation). In theory, lesions with increased epidermal melanin are accentuated and those with increased dermal melanin become less obvious (i.e. blend with uninvolved skin) with Wood’s lamp examination. However, clinicopathologic studies utilizing adjacent uninvolved skin as controls have shown that Wood’s lamp examination does not correlate with histologic findings . In addition, no completely dermal form of melasma was observed histologically when bilateral nevus of Ota-like macules, a form of dermal melanocytosis sometimes misdiagnosed as melasma (see Table 67.2 ), were excluded. Considering that epidermal pigmentation is more likely to respond to topical therapies, further studies are needed to determine the clinical utility and prognostic significance of Wood’s lamp examination.


Pathology


Compared to uninvolved adjacent skin, increased melanin deposition is observed in all layers of the epidermis, particularly the basal layer. An increased number of melanophages may also be seen in the upper dermis. Epidermal melanocytes are normal to slightly increased in number, and they are enlarged with prominent dendrites .


Ultrastructurally, lesional melanocytes contain an increased number of melanosomes. In addition, the mitochondria, Golgi apparatus, and rough endoplasmic reticulum are increased in number or amount. These findings support the theory of hyperfunctional melanocytes, presumably stimulated by UV irradiation or hormones (see Pathogenesis above).


Differential Diagnosis


The differential diagnosis of melasma is reviewed in Table 67.2 . These disorders are distinguished from melasma based upon historical aspects (e.g. drug ingestion, previous inflammation), color, distribution pattern, histologic features, and, if present, primary inflammatory lesions.


Treatment


The treatment of melasma is summarized in Table 67.3 . Diligent sun protection and patient motivation are necessary for any melasma treatment regimen to be successful. For epidermal melasma, 2 months of therapy are typically required to initiate lightening and 6 months of treatment are often needed to achieve satisfactory results.



Table 67.3

Treatment options for melasma.

HQ, hydroquinone.

















TREATMENT OPTIONS FOR MELASMA
Recommendations for all patients



  • Avoidance of sun exposure and tanning beds



  • Daily use of broad-spectrum sunscreen (ideally SPF ≥30 with physical blocker such as zinc oxide or titanium dioxide)



  • Sun-protective hats and clothing



  • Camouflage makeup



  • Discontinue oral contraceptives, if possible

Active treatment * , **



  • First-line topical therapies




    • Triple combination of HQ + retinoid + corticosteroid § at bedtime



    • 4% HQ daily, typically at bedtime



    • Azelaic acid (15–20%)




  • Adjunctive topical therapies




    • L-ascorbic acid (10–15%)



    • Kojic acid (1–4%)




  • Second-line therapies




    • Glycolic (start at 30% and increase as tolerated) or salicylic acid peels (20–30%) every 4–6 weeks




  • Third-line therapies




    • Fractional laser



    • Intense pulsed light (IPL)


Long-term maintenance



  • Continue daily sunscreen and sun-protective measures (see above)



  • Topical retinoid



  • Topical α-hydroxy acid (e.g. glycolic acid cream)



  • Other topicals, e.g. L-ascorbic acid (10–15%) , azelaic acid (15–20%), or kojic acid (1–4%)


* Results from topical treatments may take up to 6 months to appreciate; depending on the patient, HQ or a combination HQ + retinoid + corticosteroid are typically used daily for 2–4 months and then decreased in frequency to 1–2 times per week; prolonged daily use can result in side effects such as perioral dermatitis and atrophy (corticosteroid) or exogenous ochronosis (HQ; see Ch. 129 ).


** While topical HQ can cause allergic contact dermatitis, all topical agents may lead to irritant contact dermatitis, which can worsen the dyspigmentation; if this is a concern, can test on a small, non-facial site prior to widespread facial application.


§ Typically a class 5–7 topical corticosteroid is used (see Ch. 125 ).


Potential risk of post-procedural dyspigmentation; a small test site should be performed prior to widespread facial laser or light therapy.



Additional Forms of Circumscribed Hyperpigmentation


Segmental Pigmentation Disorder


This term was coined by Metzker et al. in 1983 and re-introduced by Hogeling and Frieden in 2010 . It is a type of pigmentary mosaicism, i.e. a postzygotic genetic alteration leading to a regional change in pigment production potential, that is characterized by a block-like pattern of hyper- or (less often) hypopigmentation ( Fig. 67.6 , see Ch. 62 ). The hyperpigmented patches are evident at birth or become apparent during infancy. They favor the trunk, with midline demarcation more often evident ventrally than dorsally and less distinct lateral borders. There are usually no associated extracutaneous anomalies.




Fig. 67.6


Segmental pigmentation disorder .

Unilateral block-like hyperpigmentation on the chest, abdomen, and upper arm of an infant. Note the midline demarcation inferiorly.

Courtesy, Julie V Schaffer, MD.


Familial Progressive Hyperpigmentation


Familial progressive hyperpigmentation is an autosomal dominant disorder characterized by hyperpigmented patches in a widespread distribution including the palms, soles, lips, and conjunctiva. The lesions begin to develop during infancy and increase in size, number, and confluence with age. Heterozygous gain-of-function mutations in the KIT ligand gene ( KITLG ) can cause this condition as well as familial progressive hyper- and hypopigmentation , which has the additional finding of hypopigmented macules and patches.


Primary (Localized) Cutaneous Amyloidosis


Macular and lichenoid forms of primary (localized) cutaneous amyloidosis are associated with hyperpigmentation (see Ch. 47 ). The most common locations are the upper back (macular amyloidosis) or the extensor surface of the lower extremities (lichen amyloidosis), and there is a characteristic rippled pattern with parallel bands or ridges of hyperpigmentation. Areas of involvement are often pruritic, and rubbing plays a key role in the production of lesions. Histologically, melanophages as well as amyloid deposits that stain positively with anti-keratin antibodies are seen within the upper dermis.


Mastocytosis


Cutaneous mastocytosis is a spectrum of disorders characterized by the accumulation of mast cells within the skin and sometimes in other organs (see Ch. 118 ). Urticaria pigmentosa, the maculopapular form of mastocytosis, classically features hyperpigmented lesions, with patients developing a few to several hundred brown to red–brown macules and papules. However, solitary mastocytomas can also have a light brown color. Lesions of cutaneous mastocytosis typically urticate after they are stroked (Darier’s sign), and an increased number of mast cells is seen in biopsy specimens. The cause of the hyperpigmentation in masto­cytosis may involve stimulation of melanocytes by mast cell-derived mediators such as KIT ligand (stem cell factor) or α-melanocyte-stimulating hormone . Clonal somatic activating mutations in the gene that encodes the KIT receptor often underlie mastocytosis in both children and adults. Whereas the prognosis for childhood-onset mastocytosis is good, with spontaneous resolution by adolescence in many patients, adult-onset disease is frequently persistent (see Ch. 118 ).


Tinea (Pityriasis) Versicolor


Tinea versicolor is a superficial skin infection caused by the yeast Malassezia globosa and other Malassezia spp. (see Ch. 77 ). Hypo- or hyperpigmented macules or very thin papules and plaques covered with fine scale are usually found on the upper trunk and proximal upper extremities but may also appear in other sites such as the neck, face, and groin. There is often coalescence of lesions centrally, especially on the trunk. In light and electron microscopy studies, a similar number of melanocytes was noted in uninvolved skin as in hypo- and hyperpigmented lesions; the latter had a thickened stratum corneum that contained more organisms. The clinical differential diagnosis for the hyperpigmented form of pityriasis versicolor may include PIH and confluent and reticulated papillomatosis, but a KOH preparation of the scale showing both hyphal and yeast forms of Malassezia distinguishes tinea versicolor from these entities.


Atrophoderma of Pasini and Pierini


Atrophoderma of Pasini and Pierini is usually seen in young adults and has been postulated to represent an atrophic form of morphea (see Ch. 99 ). Most often, multiple oval hyperpigmented patches measuring 4–10 cm in diameter appear on the posterior trunk. There is a subtle depression of the entire lesion, but no induration or secondary changes. The depression can be appreciated by palpation of the edge of the lesion, with a characteristic “cliff sign” at the peripheral margin.


Pigmented Lesions


Lentigines


Lentigines are reviewed in Chapters 109 and 112 .


Café-au-Lait Macules


Café-au-lait macules (CALMs) are hyperpigmented macules or patches two to three shades darker than uninvolved skin (see Ch. 112 ). They are found in at least 10% of the population. Although evident at birth in ~3% of all neonates and up to 30% of black neonates, CALMs may not become apparent until infancy or early childhood in lightly pigmented individuals. The presence of multiple CALMs raises the possibility of neurofibromatosis type 1 or another genetic syndrome (see Table 61.4 ); Fig. 61.10 outlines an approach to a young child with multiple CALMs. A CALM is usually easily distinguished from a fully developed congenital melanocytic nevus, but in infants there may be overlap in the clinical appearance of these two entities. The differential diagnosis also includes the earliest stage of a nevus spilus (before the “speckles” appear), Becker melanosis (nevus) or smooth muscle hamartoma, and a mastocytoma; in addition, segmental CALMs and “pigmentary mosaicism” have significant overlap. Although laser treatment of CALMs is possible (see Ch. 137 ), responses vary and recurrence of pigmentation is common.


Drug-Induced Hyperpigmentation or Discoloration




Key features





  • Localized or generalized hypermelanosis or discoloration may be seen



  • Several medications and drug classes are known to induce hyperpigmentation or discoloration, especially minocycline, antimalarials, chemotherapeutic agents, and zidovudine



  • Longitudinal, transverse, or diffuse melanonychia may also be present


Cutaneous hypermelanosis or discoloration can result from exposure to chemicals and a wide range of medications, most commonly chemotherapeutic agents, antimalarials, minocycline, and zidovudine ( Table 67.4 , Figs 67.7–67.9 ). The underlying mechanisms vary from induction of melanin production to deposition of drug complexes or heavy metals within the dermis. The pigmentation can be circumscribed or generalized. Although it usually resolves with discontinuation of the offending drug, the course may be prolonged. Longitudinal, transverse, or diffuse melanonychia and oral mucosal pigmentation may also be observed.

Table 67.4

Drugs and chemicals associated with hyperpigmentation or discoloration.

BCNU, 1,3-bis (2-chloroethyl)-1-nitrosourea. ACTH, adrenocorticotropic hormone; EM, electron microscopy; EPP, erythropoietic protoporphyria; MSH, melanocyte-stimulating hormone.

Adapted from Kang S, Lerner EA, Sober AJ, Levine N. In: Levine N (ed.). Pigmentation and Pigmentary Disorders. Boca Raton: CRC Press, 1993:417–31.




















































































































































DRUGS AND CHEMICALS ASSOCIATED WITH HYPERPIGMENTATION OR DISCOLORATION
Drug or chemical Clinical features Histopathology/comment
Chemotherapeutic agents
BCNU (carmustine)


  • Hyperpigmentation at sites of topical application (not with parenteral administration)




  • Hyperplasia of basal melanocytes



  • Increased melanin within the epidermis

Bleomycin (intravenous or intralesional)


  • Linear, flagellate bands that favor the trunk and may be associated with minor trauma (see text)



  • Transverse melanonychia



  • Hyperpigmentation overlying joints/pressure points or localized to striae and palmar creases



  • Sclerodermoid changes




  • Increased epidermal melanin but no increase in the number of melanocytes



  • Usually relatively few dermal melanophages

Busulfan


  • Generalized hyperpigmentation resembling Addison disease; sometimes associated with drug-induced pulmonary fibrosis




  • Increased melanin within basal keratinocytes and dermal macrophages

Cyclophosphamide


  • Diffuse hyperpigmentation of the skin and mucous membranes



  • Pigment localized to the nails (transverse, longitudinal, or diffuse melanonychia), palms and soles, or teeth




  • Cutaneous hyperpigmentation usually regresses within 6 to 12 months after therapy is discontinued

Dactinomycin


  • Generalized hyperpigmentation, most prominent on the face




  • Pigmentation fades after treatment is discontinued

Daunorubicin


  • Hyperpigmentation of sun-exposed areas



  • Transverse brown–black melanonychia

Doxorubicin


  • Hyperpigmentation overlying the small joints of the hands and involving the palms (especially the creases), soles, and oral mucosa (buccal, tongue)



  • Transverse melanonychia




  • Increased epidermal melanin



  • Increased number of melanocytes

5-Fluorouracil


  • Hyperpigmentation in sun-exposed areas (~5% of patients treated systemically; often follows an erythematous photosensitivity reaction)



  • Increased pigmentation of skin overlying veins in which the drug was infused



  • Other sites include the dorsal aspects of the hands, palms/soles, and radiation ports



  • Transverse or diffuse melanonychia; lunular pigmentation




  • Postinflammatory hyperpigmentation

Hydroxyurea


  • Reversible hyperpigmentation over pressure points and on the back



  • Longitudinal, transverse or diffuse melanonychia; lunular pigmentation




  • Lichenoid eruption with postinflammatory hyperpigmentation can also occur

Mechlorethamine (nitrogen mustard)


  • Topical use for cutaneous T-cell lymphoma may result in generalized hyperpigmentation



  • More intense in lesional skin




  • Disaggregation of melanosomes within keratinocytes



  • Increased number of melanocytes

Methotrexate


  • Uniform hyperpigmentation in sun-exposed areas (occasionally follows an erythematous photosensitivity reaction)




  • Uncommon

Antimalarials
Chloroquine, hydroxychloroquine, quinacrine


  • Gray to blue–black pigment, usually pretibial, with (hydroxy)chloroquine; face, hard palate, sclerae, and subungual areas may be involved



  • Diffuse yellow to yellow–brown discoloration with quinacrine



  • Discoloration affects up to 25% of patients




  • Dermal deposition of melanin–drug complexes; hemosiderin around capillaries



  • May fade after discontinuation of drug, but rarely resolves completely

Heavy metals
Arsenic


  • Areas of bronze hyperpigmentation ± superimposed “raindrops” of lightly pigmented skin; favors axillae, groin, palms, soles, nipples, and pressure points



  • Dyspigmentation appears 1–20 years after arsenic exposure, with a strong dose–response relationship



  • Palmoplantar keratoses and squamous cell carcinoma typically develop after dyspigmentation (see Ch. 88 )




  • Dermal and epidermal deposition of arsenic



  • Increased epidermal melanin synthesis

Bismuth


  • Generalized blue–gray discoloration of the face, neck and dorsal hands



  • Oral mucosa and gingivae may be involved




  • Bismuth granules in the papillary and reticular dermis

Gold (chrysiasis)


  • Permanent blue–gray discoloration in sun-exposed areas, particularly around the eyes




  • Gold particles within lysosomes in dermal macrophages, especially in perivascular and perieccrine areas

Iron


  • Permanent brown pigment at injection sites or in areas of application of ferric subsulfate (Monsel’s) solution as a hemostatic agent



  • Dermal hemosiderin deposits (due to lysis of extravasated red blood cells and release of their iron stores) are commonly observed in the setting of venous hypertension, in pigmented purpuric dermatoses, and as a side effect of sclerotherapy of superficial veins




  • Pigment coats collagen fibers and is deposited in dermal macrophages

Lead


  • “Lead line” in gingival margin



  • Nail discoloration




  • Lead line is due to subepithelial deposition of lead granules

Mercury


  • Slate-gray discoloration, particularly in skin folds




  • Brown–black granules free in dermis, in association with elastic fibers and within macrophages

Silver (argyria)


  • Diffuse slate-gray discoloration (see Fig. 67.7A ), increased in sun-exposed areas; occurs in settings of occupational exposure, alternative medications, or systemic absorption from use of silver sulfadiazine on extensive burns/wounds



  • The nail unit (diffuse or localized to the lunulae) and sclerae may also be affected



  • Sites of topical application, e.g. of silver sulfadiazine to burns or ulcers




  • Silver granules in the basement membrane of eccrine glands; also often seen in elastic fibers, in the tissue around hair follicles, and in arrector pili muscles; highlighted by darkfield illumination (see Fig. 67.7B )

Hormones
Oral contraceptives


  • Melasma; increased pigmentation of nipples and nevi




  • Increased melanocytes and increased melanin synthesis

ACTH/MSH (ACTH is rarely used; [NIe4-D-Phe7]-α-MSH/afamelanotide orphan drug for EPP)


  • Diffuse brown or bronze hyperpigmentation, accentuated in sun-exposed sites




  • Increased melanin synthesis

Miscellaneous compounds
Amiodarone


  • Slate-gray to violaceous discoloration of sun-exposed skin, especially the face (less common than erythema from photosensitivity)



  • Fair-skinned patients after long-term, continuous therapy




  • Yellow–brown granules in dermal macrophages, mostly in a perivascular distribution



  • By EM, lysosomal inclusions composed of a lipid-like substance



  • Usually fades completely over months to years after discontinuation of drug, but sometimes persists

Azidothymidine (zidovudine, AZT)


  • Longitudinal > transverse and diffuse melanonychia (up to 10% of patients); blue lunulae



  • Mucocutaneous hyperpigmentation (e.g. widespread diffuse, acral, oral macules); most common in patients with darkly pigmented skin, and may be accentuated in areas of friction or sun exposure




  • Skin biopsy shows increased melanin in the epidermis and dermal melanophages



  • Fades gradually after drug is discontinued

Clofazimine


  • Diffuse red to red–brown discoloration of skin, conjunctivae



  • Violet–brown to blue–gray discoloration, especially of lesional skin




  • Red color secondary to drug in fat (highly lipophilic)



  • Blue–violet color secondary to brownish granular pigment within dermal macrophages



  • By EM, phagolysosomes contain amorphous granular material and lamellar structures characteristic of lipofuscin



  • Fades gradually after discontinuation of drug

Diltiazem (rarely amlodipine)


  • Slate-gray to gray–brown discoloration of sun-exposed skin in patients with skin phototypes IV–VI; perifollicular accentuation and a reticular pattern may be observed




  • Sparse lichenoid infiltrate and numerous dermal melanophages

Dioxins


  • Hyperpigmentation may occur in sun-exposed areas



  • Chloracne is a more common skin finding




  • Rare, except in accidental exposure

Ezogabine


  • Blue–gray discoloration, most often lips, face, nail beds, and hard palate



  • Black pigment deposits on conjunctivae




  • Permanent vision changes



  • Perivascular and periadnexal intracellular deposits of coarse melanin granules

Hydroquinone


  • Hyperpigmentation in areas of application due to irritant contact dermatitis (i.e. postinflammatory) or exogenous ochronosis; the latter may also result in small “caviar-like” papules




  • In exogenous ochronosis, yellow–brown banana-shaped fibers in papillary dermis (see Fig. 67.8 ) *



  • Presumed mechanism is metabolism by melanocytes of hydroquinone into ringed structures that serve as precursors of ochronotic fibers



  • May fade upon discontinuation of hydroquinone; variable improvement with pigment-directed Q-switched lasers

Imatinib (also dasatinib)


  • Localized or diffuse hyperpigmentation (<5% of patients)



  • Diffuse melanonychia, repigmentation of gray hair, and pigmentation of the gingiva and teeth




  • Localized or diffuse hypo- or depigmentation is more common (40–60% of darkly pigmented patients)

Minocycline


  • Type I : blue–black discoloration in sites of inflammation and scars, including those due to acne or ablative laser therapy (see Fig. 127.6A )



  • Type II : blue–gray macules/patches (1 mm–10 cm in size) within previously normal skin, most often on the shins (see Figs 67.9 & 127.6B–D ); sometimes misdiagnosed as ecchymoses



  • Type III : diffuse “muddy brown” pigmentation that is most prominent in sun-exposed areas



  • Blue–black discoloration may also involve nails, sclerae, oral mucosa, bones, thyroid, and teeth




  • Iron-containing (types I, II) or melanin-containing (type II) pigment granules within the dermis ** ; the former can be intra- or extracellular and may represent hemosiderin and/or a minocycline derivative plus chelated iron



  • Increased melanin within the basal epidermis and/or dermal melanophages (type III)



  • Minocycline is a highly lipid-soluble, yellow, crystalline material that turns black with oxidation



  • Fades after discontinuation of medication, but may take months or even years; for types I and II, treatment with Q-switched pigment-directed lasers (similar to tattoo removal) may decrease the discoloration

Psoralens


  • Diffuse hyperpigmentation after exposure to UVA light following oral administration (PUVA)



  • Circumscribed or linear streaks of hyperpigmentation can be seen with topical exposure, e.g. topical PUVA or phytophotodermatitis (exposure to psoralen-containing plants plus sunlight)




  • Proliferation of follicular melanocytes, with increased synthesis and transfer of melanin



  • Singly dispersed melanosomes within keratinocytes



  • Psoralens are furocoumarin compounds originally derived from plants

Psychotropic drugs (chlorpromazine, thioridazine, imipramine, desipramine, amitriptyline)


  • Slate-gray to brown (with amitriptyline) discoloration in sun-exposed areas




  • Golden-brown granules in the upper dermis



  • Electron-dense inclusion bodies

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Sep 15, 2019 | Posted by in Dermatology | Comments Off on Disorders of Hyperpigmentation
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