(See also Overview of Pigmentation Disorders.)
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 include Addison disease, hemochromatosis, and primary biliary cholangitis. Skin findings are nondiagnostic; therefore, a skin biopsy is not necessary or helpful. The search for underlying cancer should be based on a review of systems.
Melasma consists of dark brown, sharply marginated, roughly symmetric patches of hyperpigmentation on the face (usually on the forehead, temples, cheeks, cutaneous upper lip, or nose). It occurs primarily in pregnant women (melasma gravidarum, also called 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
In women, melasma fades slowly and incompletely after childbirth or cessation of hormone use. In men, melasma rarely fades.
The mainstay of melasma management is strict sun protection. Patients should use sunscreen with a sun protection factor (SPF) of 30 or higher, wear protective clothing and hats, and avoid direct sun exposure. During and after therapy, strict sun protection must be maintained.
Other treatment depends on whether the pigmentation is epidermal or dermal; epidermal pigmentation becomes accentuated with a Wood light (365 nm) or can be diagnosed with biopsy. Only epidermal pigmentation responds to treatment. Most topical melasma treatments are used in combination rather than individually.
Triple topical therapy is first-line treatment that is often effective and consists of a combination of
Hydroquinone 2 to 4%
Tretinoin 0.05 to 1%
A class V to VII topical corticosteroid (see Table: Relative Potency of Selected Topical Corticosteroids)
Hydroquinone depigments the skin by blocking the enzymatic oxidation of tyrosine 3,4-dihydroxyphenylalanine (DOPA) and inhibiting melanocyte metabolic processes. Hydroquinone should be tested behind one ear or on a small patch on the forearm for 1 week before use on the face because it may cause irritation or an allergic reaction. Tretinoin promotes keratinocyte turnover and can exfoliate skin that contains epidermal pigment. Corticosteroids help block synthesis and secretion of melanin. Two promising technologies being tried in conjunction with triple topical therapy are the Q-switched Nd:YAG (1064 nm) laser and nonablative fractional resurfacing.
If triple topical therapy is not available, then hydroquinone 3 to 4% applied twice daily for up to 8 weeks at a time (chronic continuous use can theoretically increase the risk of exogenous ochronosis, which is a permanent form of hyperpigmentation) may be considered; 2% hydroquinone is useful as maintenance.
Azelaic acid 15 to 20% cream can be used in place of or with hydroquinone and/or tretinoin. Azelaic acid is a tyrosinase inhibitor that reduces melanin production (and is considered safe for use during pregnancy). In addition, topical kojic acid has been increasingly used; it is a chelating agent that blocks tyrosine conversion to melanin.
Second-line treatment options for patients with severe melasma unresponsive to topical bleaching agents include chemical peeling with glycolic acid or 30 to 50% trichloroacetic acid. Laser treatments also have been used but are not standard therapy.
Oral therapies have been studied. A recent randomized study has shown improvement with oral tranexamic acid in patients with moderate-to-severe melasma (1).
1. Del Rosario E, Florez-Pollack S, Zapata L Jr, et al: Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol 78(2):363–369, 2018. doi: 10.1016/j.jaad.2017.09.053
Lentigines (singular: lentigo) are flat, tan to brown, oval macules. They are commonly due to chronic sun exposure (solar lentigines; sometimes called liver spots but are not related to hepatic dysfunction) 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 (or LEOPARD syndrome, which stands for multiple Lentigines, Electrocardiogram [ECG] conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitals, Retardation of growth, and sensorineural Deafness), or xeroderma pigmentosum.
Changes are usually diffuse but sometimes have drug-specific distribution patterns or hues (see Table: Hyperpigmentation Effects of Some Drugs and Heavy Metals). Mechanisms include
Increased melanin in the epidermis (tends to be more brown)
Increased 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 Heavy Metals
In fixed drug eruptions, red plaques or blisters form at the same site each time the causative drug is taken; residual postinflammatory hyperpigmentation usually persists, especially in darker skin types. Typical lesions occur on the face (especially the lips), hands, feet, and genitals. Typical inciting drugs include antibiotics (sulfonamides, tetracyclines, trimethoprim, and fluoroquinolones), nonsteroidal anti-inflammatory drugs, and barbiturates.
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 disorders such as 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.