Acquired hyperpigmentation disorders

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 [6] due to the limited efficacy of available treatments.

This topic will review the approach to 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".)

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].

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 [8]. Each melanocyte is associated with approximately 36 basal keratinocytes to form the so-called epidermal melanin unit.

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 [9,10]. 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 [11].

PATHOPHYSIOLOGY OF HYPERPIGMENTATION

Hypermelanosis — Skin hyperpigmentation is, in most cases, caused by increased biosynthesis and deposition of melanin in the epidermis (basal and suprabasal layers) and/or in the dermis [12,13]. 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?

●If not present at birth, was the disorder onset in childhood or adolescence?

●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 smoking habits and 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 [14]. 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 [15,16]:

●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 [17]. 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 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 [18]. 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 [19,20].

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 [21,22].

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 or there is suspicion for malignancy. 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).

WHEN TO REFER — Patients with persistent or extensive areas of abnormal skin hyperpigmentation that does not follow a common clinical pattern or does not respond to first-line treatments should be referred to a board-certified dermatologist for further evaluation and management.

CIRCUMSCRIBED HYPERPIGMENTATION

Onset in childhood/adolescence

Ephelides (freckles) — 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 can 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 [23,24].

Ephelides are benign lesions and have no propensity for malignant transformation [25]. 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 [26]. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Ephelides (freckles)'.)

Simple lentigines — Simple lentigines (lentigo simplex) 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'.)

Partial unilateral lentiginosis — Partial unilateral lentiginosis is a rare disorder characterized by the presence of multiple lentigines arising on normally pigmented skin in a unilateral or segmental pattern [27]. Partial unilateral lentiginosis is an acquired disorder in most cases, with lentigines first appearing during childhood or adolescence [28]. 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, partial unilateral lentiginosis 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'.)

Laser treatment with alexandrite quality-switched (Q-switched) laser or Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser has been used in a few patients with partial unilateral lentiginosis with good results [31,32].

Café-au-lait macules — Café-au-lait macules (CALM) present as uniform, light-brown, well-demarcated macules or patches that may be present at birth or become evident later in childhood.

Becker melanosis — Becker melanosis, also called Becker 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 2A-B). In one-half of the cases, there is an associated hypertrichosis. The diagnosis, differential diagnosis, and management of Becker nevus are discussed elsewhere. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Becker nevus'.)

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 [33]. It presents with a gradually progressive, reddish-brown pigmentation surmounted by small follicular papules (picture 3) [34]. 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 [33,35,36]. Complete regression is difficult to achieve, and relapse is common.

Idiopathic eruptive macular pigmentation — Idiopathic eruptive macular pigmentation is an exceedingly rare condition of unknown etiology that presents predominantly in children and adolescents with the eruption of asymptomatic, brown macules on the face, neck, proximal extremities, and trunk [37-39]. Histologically, there is a basal layer hyperpigmentation with dermal melanophages; some specimens may show papillomatosis [37,40].

The diagnosis is based upon history and clinical and histopathologic findings. 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 [37,38].

Most patients will undergo spontaneous clearance in months to years [37].

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 [41,42].

Lesions typically involve the neck, ankle (posterior to the medial or lateral malleolus), and face but may also occur on other body areas (picture 4A-B). Diagnosis and treatment can be achieved by removing lesions with gentle isopropyl alcohol swabbing, with once-a-week application as prophylaxis.

Actinic lichen planus — Actinic lichen planus (ALP), also known as lichen planus tropicus, is a rare photodistributed variant of lichen planus most commonly seen in children and young adults from the Middle East, East Africa, or India [43-45]. Its pathogenesis is unknown, but exposure to UV radiation appears to have a precipitating effect. (See "Lichen planus".)

ALP usually presents as melasma-like, hyperpigmented patches or red-brown plaques with an annular configuration [46]. 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 "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis" and "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus' and "Polymorphous light eruption".)

Multiple therapies in combination with sunscreens have been tried in individual patients with ALP with varying outcomes. These include photoprotection, topical and intralesional corticosteroids, antimalarials, acitretin, and cyclosporin [44,47-49].

Onset in adulthood

Lentigines

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 5A-B), dorsal aspect of hands (picture 6) and forearms, upper chest (picture 7), and upper back (picture 8), 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, and laser therapy [50]. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Lentigines'.)

PUVA 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 [51]. Similar macules have been noted in patients with mycosis fungoides treated with narrowband ultraviolet B (UVB) phototherapy [52].

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 9), and lentigines of the buccal mucosa, face, hands, and feet [53]. Approximately two-thirds of the patients are of Japanese descent [54].

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. Medical treatment has included nutritional support, systemic corticosteroids, conventional immunosuppressant agents, H2-receptor antagonists, and anti-TNF agents [55]. Regardless of therapy, the mortality rate exceeds 50 percent. (See "Overview of colon polyps", section on 'Cronkhite-Canada syndrome'.)

Dermatosis papulosa nigra — Dermatosis papulosa nigra (DPN) is a common benign condition characterized by lesions considered 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 (picture 10A-B). 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 [56,57].

The pathogenesis of DPN is unknown. Studies have found mutations in fibroblast growth factor receptor 3 and phosphatidylinositol 3-kinase genes [58]. 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 electrodesiccation and curettage, cryotherapy, snip removal (for pedunculated lesions), and laser therapy [59,60]. Lasers used for DPN include long-pulsed 1064 nm Nd:YAG laser, 532 nm diode laser, pulsed dye laser, nonablative 1550 nm fractionated laser, potassium titanyl phosphate (KTP) laser, and carbon dioxide (CO₂) ablative laser [61-67].

Maturational hyperpigmentation — Darkening of facial skin tone is frequently seen in older individuals with darkly pigmented skin. Maturational hyperpigmentation or maturational dyschromia are terms that refer to a primary darkening of both mature and sun-exposed skin [68]. 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 11). (See "Photoaging".)

The etiopathogenesis of maturational hyperpigmentation remains unclear. Chronic sun exposure is likely implicated; obesity and diabetes have been postulated as predisposing factors [68]. 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 mostly 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 [69]. 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 [70]. A familial form has also been recognized, with variable clinical expression in different members of the family [71]. 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 [11,69,70].

Excessive sun exposure, drugs, hormonal causes, and extension of pigmentary demarcation lines may be additional contributing factors [72]. Histologically, there is an increase in dermal melanin and hemoglobin [73,74].

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 [75], lasers [76-78], autologous fat transplantation, fat grafting with and without blepharoplasty [79,80], and dermal fillers [81] 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 (picture 12A-B). It is most common in female individuals with darkly pigmented skin who live in areas of intense ultraviolet (UV) radiation exposure [82]. The clinical features, diagnosis, and management of melasma are discussed in detail separately. (See "Melasma: Management".)

Poikiloderma of Civatte — Poikiloderma of Civatte 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 [83]. The submental area is typically spared. Poikiloderma of Civatte is usually seen in individuals older than 40 years with lightly pigmented skin and is more common in females.

Histologically, poikiloderma of Civatte 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 [84].

Poikiloderma of Civatte 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 [85-88] and nonablative fractional laser. (See "Laser and light therapy for cutaneous vascular lesions" and "Laser and light therapy for cutaneous hyperpigmentation".)

Acquired dermal macular hyperpigmentation — "Acquired dermal macular hyperpigmentation" is an umbrella term that includes disorders clinically described by variably sized, pigmented macules and patches with histologic evidence of pigment incontinence. These diseases include erythema dyschromicum perstans/ashy dermatosis, lichen planus pigmentosus, Riehl melanosis/pigmented contact dermatitis, and idiopathic eruptive macular pigmentation [89].

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 [90]. Most patients with this disorder are from Latin America. EDP is usually seen in young adults, but it may also occur in children [91].

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 [92-94]. However, in most cases, a cause or trigger cannot be identified. HLA-DR4 allele may be a risk factor for EDP in Mexican patients [95].

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 [96]. 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 [46,90]. 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 14A-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 15), 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 [97], dapsone [98], clofazimine [99,100], and isotretinoin [101] has been reported in a small number of patients. Sustained resolution with narrowband UVB has been reported in one patient [102].

The disease is slowly progressive and persistent. Spontaneous resolution over months to years has been reported in children [103].

Lichen planus pigmentosus — Lichen planus pigmentosus is a chronic and progressive disorder of unknown etiology that occurs predominantly in the third to fifth decade of life. Lichen planus pigmentosus is more prevalent in individuals from India, Latin America, and the Middle East [104]. 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 [105,106].

Although traditionally considered a variant of lichen planus, lichen planus pigmentosus is considered by many experts as a separate entity [89]. However, some patients may exhibit concurrent findings of lichen planus [105,107]. (See "Lichen planus".)

There are multiple reports of the coexistence of lichen planus pigmentosus and frontal fibrosing alopecia, illustrating that lichen planus pigmentosus may be the herald sign of this scarring type of hair loss and that both entities may have a pathogenic link [108,109]. (See "Lichen planopilaris", section on 'Frontal fibrosing alopecia'.)

Lichen planus pigmentosus typically presents with asymptomatic, oval or irregularly shaped, brown to gray-brown macules and patches in sun-exposed areas, including the forehead, temples, and neck (picture 16). It may also occur on the trunk and in intertriginous areas (lichen planus pigmentosus inversus) [89]. In contrast with erythema dyschromicum perstans, early lichen planus pigmentosus lesions lack an erythematous border. (See 'Erythema dyschromicum perstans' above.).

The diagnosis of lichen planus pigmentosus is based on clinical and histologic findings. Histopathology shows prominent dermal melanophages with or without features of interface dermatitis. The differential diagnosis includes lichen planus, erythema dyschromicum perstans, melasma, lichenoid drug eruptions, and postinflammatory hyperpigmentation.

Lichen planus pigmentosus 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 [110-114]. (See "Lichen planus", section on 'Treatment'.)

Riehl's melanosis (pigmented contact dermatitis) — Riehl's melanosis or pigmented contact dermatitis is a dermal melanosis involving the face and neck caused by repeated contact with cosmetic ingredients [115]. A mild erythema and pruritus typically precede the development of a diffuse or reticulated hyperpigmentation (picture 17). 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 [116]. 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 [73]. (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.

Idiopathic eruptive macular pigmentation — (See 'Idiopathic eruptive macular pigmentation' above.)

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 [34]. 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 [117,118].

The pigmentation tends to be persistent. Treatment is difficult and involves sun avoidance and the use of skin-lightening agents [119].

Nevus of Hori — Acquired bilateral nevus of Ota-like macules, 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 [120-122]. 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 [121]. 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 [123-127]. Adverse effects of treatment include postinflammatory hypo- and hyperpigmentation. (See "Laser and light therapy for cutaneous hyperpigmentation".)

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 18A-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 is a pigmentary disorder presenting in older individuals, predominantly in females, with large, geographic, gray-brown patches localized to the forearms, usually in a bilateral distribution [128]. 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 acquired brachial cutaneous dyschromatosis 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, acquired brachial cutaneous dyschromatosis is thought to be a manifestation of chronic sun damage [129].

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 [130,131]. The highest incidence is reported in African countries, due to the widespread use of these agents [132,133]. (See "Topical skin-lightening agents: Complications of use in the nonmedical setting", section on 'Exogenous ochronosis'.)

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 19A-B)). 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 [134].

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 [130,135-140].

Hyperpigmentation of the oral mucosa

Physiologic hyperpigmentation — Physiologic hyperpigmentation of the oral cavity occurs frequently in individuals with darkly pigmented skin, is asymptomatic, and does not require treatment. Oral pigmentation can be found along the lower vermillion border, tongue, oral mucosa, palate, and commonly along the attached gingiva.

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 20) or on the oral mucosa, more often on the gingiva (picture 21) and hard palate (picture 22). 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. (See "Oral lesions", section on 'Oral melanotic macules'.)

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.

Oral mucosal melanoma — Mucosal melanoma is a rare, aggressive malignancy that carries a very poor prognosis [141]. It typically presents as an asymptomatic, brown to black macule or patch located in the maxillary gingival or palatal mucosa (picture 23). Lesions often have irregular borders and may be ulcerated. Biopsy is required for diagnosis. (See "Oral lesions", section on 'Melanoma'.)

Laugier-Hunziker syndrome — Laugier-Hunziker syndrome (also called idiopathic lenticular mucocutaneous pigmentation) is an acquired, benign disorder presenting in adults with lentigines on the lips and buccal mucosa (picture 24). Approximately one-half of the patients also have longitudinal melanonychia and macular pigmentation of the genitals [142] (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

●Inherited diseases associated with lentiginosis (eg, Peutz-Jeghers syndrome, LEOPARD [lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness] syndrome, Carney complex) (see "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "Congenital and inherited hyperpigmentation disorders", section on 'LEOPARD syndrome' and "Carney complex")

●Cronkhite-Canada syndrome (see 'Cronkhite-Canada syndrome' above)

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, Nd:YAG lasers, and the Q-switched alexandrite laser have been used in single case reports [143-145]. (See "Laser and light therapy for cutaneous hyperpigmentation", section on 'Lentigines'.)

Smoker's melanosis — Smoker's melanosis is characterized by irregular macular hyperpigmentation of the oral mucosa secondary to tobacco smoking [146-148]. 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 [147]. 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 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 [149].

PATTERNED 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 exposure pattern of 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 25A-B). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phytophotodermatitis'.)

Drug-induced linear hyperpigmentation

Serpentine supravenous hyperpigmentation — Serpentine supravenous hyperpigmentation describes a pigmentary pattern that follows the course of an underlying vein proximal to an infusion site [150]. 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) [151,152]. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Patterned hyperpigmentation (serpentine, flagellate, reticular)'.)

Flagellate hyperpigmentation — Flagellate hyperpigmentation, also called flagellate erythema, is a characteristic cutaneous reaction to treatment with bleomycin [153,154]. Multiple linear, erythematous or hyperpigmented streaks appear arising at sites of scratching or other minor traumas to the skin (picture 26). 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. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Patterned hyperpigmentation (serpentine, flagellate, reticular)'.)

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 [155,156]. Diltiazem and topical benzoyl peroxide have also been reported as a cause. Diffuse reticulate hyperpigmentation develops predominantly 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. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Patterned hyperpigmentation (serpentine, flagellate, reticular)'.)

Erythema ab igne — Erythema ab igne is a reticular, erythematous, pigmented dermatosis seen predominantly in adults 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 [157]. 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 27A-C), heated car seats, and among laptop users who hold computers on their thighs [158-162].

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 [163]. However, longstanding lesions may be associated with permanent hyperpigmentation (picture 27A-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 28A-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".)

Prurigo pigmentosa — Prurigo pigmentosa (PP; also called Nagashima disease and "keto rash") is a rare inflammatory skin disorder characterized by chronic, recurrent, pruritic skin lesions that leave a postinflammatory reticular hyperpigmentation [164,165]. Although PP has been reported most frequently in individuals from East Asia, it has been described in Europe, Australia, North America, and Middle East [166,167]. In a review of 369 cases, the mean age at onset was 26 years (range 13 to 72), with a female predominance (72 percent [167]).

The cause of PP is unknown. Risk factors include diabetic ketoacidosis, diet with carbohydrate restriction ("ketogenic diet"), fasting, cloth friction, and contact sensitization to metals.

PP presents with erythematous urticarial papules arranged in a reticular pattern that evolve to crusted papules, papulovesicles and vesicles and finally to a reticulate hyperpigmentation. Predilection sites are the chest, back, and neck in symmetrical distribution [165,168].

Histopathological features of PP are nonspecific and include mild spongiosis and a dermal inflammatory infiltrate with infiltrate of lymphocytes and neutrophils [165]. Immunohistochemistry shows a dermal infiltrate of T cells predominantly expressing a T cytotoxic phenotype (CD8⁺/CD4^-) with intraepidermal lymphocytic exocytosis. Intraepidermal neutrophils and isolated necrotic keratinocytes can also be seen.

The diagnosis of PP is based on careful history, clinical presentation, and histopathologic findings. The differential diagnosis of PP includes pigmented contact dermatitis, confluent reticulated papillomatosis, and Dowling-Degos disease.

Treatment of PP includes diet modification in patients presenting with ketosis and oral tetracyclines.

In a systematic review that included 343 patients with PP for whom information on treatment was available, 38 percent received minocycline or doxycycline, with complete resolution in approximatively 50 percent of patients; the average time to resolution was 34 days for minocycline and 23 days for doxycycline [167]. Recurrence was reported in 10 percent of patients after stopping treatment.

DIFFUSE NONPATTERNED HYPERPIGMENTATION

Drug-induced — A wide variety of drugs and chemicals can lead to diffuse cutaneous hyperpigmentation [169-171]. 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.

Associated with endocrine, metabolic, and autoimmune diseases

Addison disease — Addison disease (primary adrenal insufficiency) is a clinical syndrome caused by glucocorticoid, mineralocorticoid, and in females, androgen deficiency [172]. 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 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 29).

Normally hyperpigmented skin areas, such as the nipples and genitals, become darker. The buccal, conjunctival, and genital mucosa may also be involved (picture 30). The nails and hair may also darken (picture 31). (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Hyperpigmentation'.)

The evaluation of suspected Addison 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 "Determining the etiology 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 [173,174].

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 32).

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 [173]. 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, posterior neck (picture 33), and, less commonly, the face. Histologically, it is characterized by hyperkeratosis, epidermal papillomatosis, and slight, variable acanthosis, with normal melanocyte density [173]. 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 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 [175]. (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 [176-178]. 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".)

Primary cutaneous amyloidosis — Primary cutaneous amyloidosis is a form of localized, organ-specific amyloidosis in which the amyloid deposition is limited to the skin. (See "Cutaneous manifestations of amyloidosis".)

The pathogenesis of primary cutaneous amyloidosis is not fully understood. Prolonged friction from clothing, genetic predisposition, chronic itch-scratching cycle, and sun exposure have been proposed as possible etiologic factors, but their role remains inconclusive [179,180]. The origin of the precursor protein in primary cutaneous amyloidosis is also unclear. One hypothesis is that the fibrillar amyloid deposits are derived from keratin intermediate filament proteins [181].

The most common types of primary cutaneous amyloidosis are macular amyloidosis, lichen amyloidosis, and biphasic amyloidosis [182]:

●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 34A-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 35A-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 [183]. It is characterized by reticular hyperpigmentation with hypopigmented macules distributed over nearly all of the body (picture 36).

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 [184], systemic retinoids [185], thalidomide [186], cyclosporine [187], low-dose cyclophosphamide, and narrowband ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA) phototherapy [188]. Combination treatment (eg, ultraviolet A1 [UVA1] phototherapy and high-potency topical corticosteroids) may provide optimum results [189].

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 [34,190]. 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 [191,192]. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

Histologic examination of hyperpigmented lesions shows increased basal pigmentation, pigmentary incontinence, and melanophages (picture 37) [34,190,192]. These findings support the hypothesis that the hypermelanosis associated with chikungunya fever is a form of postinflammatory hyperpigmentation.

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 38A-B) [193]. 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 [194].

Lesions may persist for three to six months after the infection [190]. Treatment involves sun avoidance and the use of topical corticosteroids [190].

Diffuse melanosis cutis — Diffuse melanosis cutis is a rare presentation of metastatic melanoma characterized by a diffuse, blue-gray discoloration of the skin and mucosae (picture 39) [195,196]. Darkening of the urine (melanuria) is often associated with diffuse melanosis cutis.

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.

Diffuse melanosis cutis 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 [196,197].

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 [198]. 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. (See 'Ultraviolet and visible light protection' below and 'Cosmetic camouflage' below.)

Ultraviolet and visible light 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 [199]. (See "Selection of sunscreen and sun-protective measures".)

Cosmetic camouflage — Physical-blocking opaque sunscreens and cosmetic coverups (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 [26]. 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 – In most cases, skin hyperpigmentation is 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

•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.)

●Specific disorders – Characteristics of specific disorders and their evaluation are described above. (See 'Circumscribed hyperpigmentation' above and 'Onset in childhood/adolescence' above and 'Onset in adulthood' above and 'Patterned hyperpigmentation' above and 'Diffuse nonpatterned 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 from both ultraviolet and visible light, cosmetic camouflage, and a variety of pigment-reduction modalities, including topical skin-lightening agents and laser therapy. (See 'General principles of treatment' above.)