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By Shinjita Das, MD, Instructor in Dermatology; Assistant in Dermatology, Harvard Medical School; Massachusetts General Hospital

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Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition.

Focal hyperpigmentation is most often postinflammatory in nature, occurring after injury (eg, cuts and burns) or other causes of inflammation (eg, acne, lupus). Focal linear hyperpigmentation is commonly due to phytophotodermatitis, which is a phototoxic reaction that results from ultraviolet light combined with psoralens (specifically furocoumarins) in plants (eg, limes, parsley, celery—see Chemical photosensitivity). Focal hyperpigmentation can also result from neoplastic processes (eg, lentigines, melanoma), melasma, freckles, or café-au-lait macules. Acanthosis nigricans causes focal hyperpigmentation and a velvety plaque most often on the axillae and posterior neck.

Diffuse hyperpigmentation can result from drugs and also has systemic and neoplastic causes (especially lung carcinomas and melanoma with systemic involvement). After eliminating drugs as a cause of diffuse hyperpigmentation, patients should be tested for the most common systemic causes. These causes are Addison disease, hemochromatosis, and primary biliary cholangitis. Skin findings are nondiagnostic; therefore, a skin biopsy is not necessary or helpful.

Melasma (chloasma)

Melasma consists of dark brown, sharply marginated, roughly symmetric patches of hyperpigmentation on the face (usually on the forehead, temples, cheeks, upper lip, or nose). It occurs primarily in pregnant women (melasma gravidarum, or the mask of pregnancy) and in women taking oral contraceptives. Ten percent of cases occur in nonpregnant women and dark-skinned men. Melasma is more prevalent among and lasts longer in people with dark skin.

Because melasma risk increases with increasing sun exposure, the mechanism probably involves overproduction of melanin by hyperfunctional melanocytes. Other than sun exposure, aggravating factors include

  • Autoimmune thyroid disorders

  • Photosensitizing drugs

In women, melasma fades slowly and incompletely after childbirth or cessation of hormone use. In men, melasma rarely fades.

Treatment depends on whether the pigmentation is epidermal or dermal; epidermal pigmentation becomes accentuated with a Wood light or can be diagnosed with biopsy. Only epidermal pigmentation responds to treatment. First-line therapy, often effective, includes a combination of hydroquinone 2 to 4%, tretinoin 0.05 to 1%, and a class V to VII topical corticosteroid (see Table: Relative Potency of Selected Topical Corticosteroids). Hydroquinone 3 to 4% applied twice daily is usually required for long courses; 2% hydroquinone is useful as maintenance. Hydroquinone should be tested behind one ear or on a small patch on the forearm for 1 wk before use on the face because it may cause irritation or an allergic reaction. Azelaic acid 15 to 20% cream, can be used in place of or with hydroquinone and/or tretinoin. Hydroquinone, tretinoin, and azaleic acid are bleaching agents.

Chemical peeling with glycolic acid or 30 to 50% trichloroacetic acid is an option for patients with severe melasma unresponsive to topical bleaching agents. Laser treatments have been used, but none has been established yet as standard therapy. Two promising technologies are the Q-switched Nd:YAG (1064 nm) laser and nonablative fractional resurfacing in conjunction with triple topical therapy. During and after therapy, strict sun protection must be maintained.


Lentigines (singular: lentigo) are flat, tan to brown, oval macules. They are commonly due to chronic sun exposure (solar lentigines; sometimes called liver spots) and occur most frequently on the face and back of the hands. They typically first appear during middle age and increase in number with age. Although progression from lentigines to melanoma has not been established, lentigines are an independent risk factor for melanoma. If lentigines are a cosmetic concern, they are treated with cryotherapy or laser; hydroquinone is not effective.

Nonsolar lentigines are sometimes associated with systemic disorders, such as Peutz-Jeghers syndrome (in which profuse lentigines of the lips occur), multiple lentigines syndrome (Leopard syndrome), or xeroderma pigmentosum.

Drug-induced hyperpigmentation

Changes are usually diffuse but sometimes have drug-specific distribution patterns or hues (see Table: Hyperpigmentation Effects of Some Drugs and Chemicals). Mechanisms include

  • Increased melanin in the epidermis (tends to be more brown)

  • Melanin in the epidermis and high dermis (mostly brown with hints of gray or blue)

  • Increased melanin in the dermis (tends to be more grayish or blue)

  • Dermal deposition of the drug, metabolite, or drug–melanin complexes (usually slate or bluish gray)

Drugs may cause secondary hyperpigmentation. For example, focal hyperpigmentation frequently occurs after drug-induced lichen planus (also known as lichenoid drug eruption).

Hyperpigmentation Effects of Some Drugs and Chemicals





Slate-gray to violaceous discoloration of sun-exposed areas; yellowish brown deposits in the dermis


Yellow-brown to gray to bluish black discoloration of pretibial areas, face, oral cavity, and nails; drug–melanin complexes in the dermis; hemosiderin around capillaries


Flagellate hyperpigmented streaks on the back, often in areas of scratching or minor trauma

Cancer chemotherapy drugs, including busulfan, cyclophosphamide, dactinomycin, daunorubicin, and 5-fluorouracil (5-FU)

Diffuse hyperpigmentation



Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis


Bluish black discoloration of ear cartilage and face after years of use

Phenothiazines, including chlorpromazine

Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis

Tetracyclines, particularly minocycline

Grayish discoloration of teeth, nails, sclerae, oral mucosa, acne scars, face, forearms, and lower legs

Heavy metals


Blue-gray discoloration of face, neck, and hands


Blue-gray deposits around the eyes (chrysiasis)


Slate-gray discoloration of skinfolds


Diffuse slate-gray discoloration (argyria), especially in sun-exposed areas

In fixed drug eruptions, red plaques or blisters form at the same site each time a drug is taken; residual postinflammatory hyperpigmentation usually persists. Typical lesions occur on the face (especially the lips), hands, feet, and genitals. Typical inciting drugs include sulfonamides, tetracycline, NSAIDs, barbiturates, and carbamazepine.

Key Points

  • Common causes of focal hyperpigmentation include injury, inflammation, phytophotodermatitis, lentigines, melasma, freckles, café-au-lait macules, and acanthosis nigricans.

  • Common causes of widespread hyperpigmentation include melasma, drugs, cancers, and other systemic disorders.

  • Test patients who have widespread hyperpigmentation not caused by drugs for primary biliary cholangitis, hemochromatosis, and Addison disease.

  • Treat melasma initially with a combination of hydroquinone 2 to 4%, tretinoin 0.05 to 1%, and a class V to VII topical corticosteroid.

  • If lentigines are a cosmetic concern, treat with cryotherapy or laser.

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