Facial hyperpigmentation: causes and treatment N.A. Vashi 1 and R.V. Kundu 2

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1 REVIEW ARTICLE Facial hyperpigmentation: causes and treatment N.A. Vashi 1 and R.V. Kundu 2 BJD British Journal of Dermatology 1 Department of Dermatology, Boston University School of Medicine, Boston Medical Center, 609 Albany St J602, Boston, MA, 02118, U.S.A. 2 Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N. St Clair Street Suite 1600, Chicago, IL,60611, U.S.A. Summary Correspondence Neelam A. Vashi. nvashi@bu.edu Accepted for publication 11 June 2013 Funding sources This supplement was kindly sponsored by L Oreal Research & Innovation and Beiersdorf. Conflicts of interest None declared DOI /bjd By midcentury, the U.S.A. will be more ethnically and racially diverse. Skin of colour will soon constitute nearly one-half of the U.S. population, and a full understanding of skin conditions that affect this group is of great importance. Structural and functional differences in the skin, as well as the influence of cultural practices, produce variances in skin disease and presentation based on skin type. In the skin of colour population, dyschromia is a growing concern, and a top chief complaint when patients present to the physician. A thorough understanding of the aetiology and management strategies of facial hyperpigmentation is of importance in caring for those afflicted and also in the development of new therapies. What s already known about this topic? In the skin of colour population, facial hyperpigmentation is a common and growing concern when presenting to the physician. Facial hyperpigmentation can cause significant cosmetic disfigurement with subsequent emotional impact. Therapy continues to be challenging as there is no universally effective treatment. Existing agents have varying degrees of efficacy and potential risk of postinflammatory hyperpigmentation with different treatment protocols. What does this study add? Persons of colour will soon comprise a majority of the international and domestic populations. A comprehensive knowledge and approach to assessment and treatment is necessary to care properly for skin of colour patients. This review thoroughly discusses aetiologies of facial hyperpigmentation and categorizes appropriate treatment strategies. Skin of colour, also known as ethnic skin, constitutes a wide range of racial and ethnic groups traditionally referring to persons of African, Asian, Native American, Middle Eastern and Hispanic backgrounds. By 2050, nearly one-half of the U.S. population will be nonwhite. 1 These skin types are generally categorized as Fitzpatrick types IV VI, and are more richly pigmented. Structural and functional differences in the skin, as well as the influence of cultural practices, produce variances in skin disease, presentation and treatment based on skin type. Darker skin phenotypes are characterized by higher content of melanin, higher eumelanin to pheomelanin ratio, and more effective distribution of melanin for protection against ultraviolet (UV) radiation. 2 In skin of colour, the amount and epidermal distribution of melanin is an important biological feature. 3 5 Melanin is not a single compound; rather, it is a mixture of biopolymers synthesized by melanocytes located in the basal layer of the epidermis. 2 Based on their chemical composition, melanins are broadly classified into two types: eumelanin and pheomelanin. 2 Multiple studies have reported that individuals with darker skin have higher total melanin content, and a higher amount of eumelanin than lighter-skinned individuals. 2 Furthermore, studies on cultured human melanocytes have 41

2 42 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu demonstrated that melanocytes derived from darker skin have higher total melanin and eumelanin contents, and a higher ratio of eumelanin to pheomelanin, than those derived from lighter skin. 2,6 Pheomelanin differs from eumelanin in its biological behaviour, importantly in the ability of pheomelanin to activate oxygen resulting in the formation of the superoxide radical anion. 2,7,8 These properties may be responsible for the high phototoxic potential of pheomelanin, which may contribute to the occurrence of photoinduced malignancies in lighter-skinned individuals. Biosynthesis of melanin occurs within the melanosome, a lysosome-like organelle and metabolic unit of the melanocyte, where melanin granules are synthesized using the amino acid tyrosine as the major substrate. 3 5,9 Variations in the number, size and aggregation of melanosomes within the melanocyte and keratinocyte contribute to racial and ethnic differences. 10 For example, darker skin types have nonaggregated and larger melanosomes. 3,11 There are no racial differences in the overall number of melanocytes; however, melanocyte number may differ by anatomical location. 10,12,13 For example, the head and forearm have the highest numbers of melanocytes. 8 Total melanin content is also greater in individuals with darker skin types. 3,14 Melanin is the major determinant of colour in the skin. The concentration of epidermal melanin in melanosomes is double in darker skin types compared with lightly pigmented skin types. 5 In addition, melanosome degradation within the keratinocyte is slower in darkly pigmented skin when compared with lighter skin types. 15 The melanin content and melanosomal dispersion pattern is thought to confer protection from damage induced by UV radiation. 3,16 Kaidbey et al. 16 demonstrated that black epidermis, on average, provides a sunprotection factor (SPF) of 134. Although the increased melanin provides protection from harmful effects of UV radiation, including photodamage and skin cancers, it also makes darkly pigmented skin more vulnerable to postinflammatory dyspigmentation. Given these functional and structural differences, common conditions may require special considerations in ethnic skin. Additionally, there are many skin conditions relatively unique to persons with skin of colour. The aim of this review is to summarize what is currently known about facial hyperpigmentation as it relates to those with skin of colour. Table 1 summarizes causes of facial hyperpigmentation. Methods We identified relevant articles by the systematic search of scientific and medical electronic search engines (PubMed, ). Key terms for searches included: dyschromia, postinflammatory hyperpigmentation, facial hyperpigmentation, hyperpigmentation, melasma, naevus of ota, ephelides, lentigines, ochronosis, melanosis, dark skin, melanin, acanthosis nigricans, skin lightening, depigmentation, hydroquinone, retinoid, kojic acid, azelaic acid, niacinamide, glycolic acid, N-acetylglucosamine, lignin peroxidase, chemical peels, peeling, dermabrasion and laser. Causes of facial hyperpigmentation Postinflammatory hyperpigmentation Postinflammatory hyperpigmentation (PIH) refers to the darkening of skin that occurs after an inflammatory eruption or cutaneous injury. The hyperpigmentation results from the melanocytes response to the cutaneous insult, which causes an increased production and/or redistribution of melanin. Patients of darker skin are predisposed to this pigment alteration. Postinflammatory changes can occur both in the epidermis and dermis. In the epidermal form of hyperpigmentation, there is increased melanin production and/or transfer to keratinocytes. In dermal PIH, a damaged basement membrane allows melanin to enter the dermis, where it is phagocytosed by dermal macrophages, referred to as melanophages. Macrophages may also migrate into the epidermis, phagocytose melanosomes, and then return to the dermis. 17,18 Melanin within dermal melanophages may persist for years. As the skin in darker patients recovers from an acute inflammatory disease, it may become hyperpigmented (PIH) or hypopigmented (known as postinflammatory hypopigmentation). Lightening or darkening of the skin is associated with many primary disorders including but not limited to discoid lupus erythematosus, seborrhoeic dermatitis, tinea versicolor, atopic dermatitis and sarcoidosis (Fig. 1). History may include any type of prior inflammation or injury, e.g. acne, arthropod assault, viral exanthems, eczema, psoriasis, trauma. Physical examination findings include small to large hyperpigmented macules and patches of varying size in any distribution. Although usually a clinical diagnosis, difficult cases can be aided with a biopsy for histopathological evaluation. Disorders such as melasma, morphoea, atrophoderma and other rarer aetiologies should be considered in patients without evidence of preceding inflammation by history or examination. The time required for the dyspigmentation to normalize is highly variable and relates to many factors including the patient s baseline skin tone, the type and intensity of the injury or inflammation, and the patient s sun-exposure habits. The time can take years and can be psychologically distressing. Treatments with skin-lightening agents, chemical peeling agents and lasers can be tried; however, they can also result in worsening of the original dyspigmentation and should always be used with caution. Maturational dyschromia Darkening of facial skin tone, even outside of extensive sun exposure, can be seen in mature dark skin. Maturational dyschromia, or a general uneven tone, can be described as diffuse hyperpigmentation that generally occurs on the lateral forehead and cheekbones (Fig. 2). One survey found that uneven skin tone was a chief complaint in more than one-third of black women. 19 These changes in skin tone probably occur from chronic sun exposure over many years. Maturational dys-

3 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 43 Table 1 Hyperpigmentary disorders of the face: distinguishing features and treatments Disease Distinguishing features Treatment Postinflammatory hyperpigmentation History or presence of inflammation with erythema and/or scaling Skin-lightening agents, chemical peeling agents and laser Maturational dyschromia Darkening of malar cheeks and forehead in mature richly pigmented skin Skin-lightening agents, antioxidants, sunscreen, microdermabrasion or chemical peels Periorbital hyperpigmentation Darkening around the eyes Skin-lightening agents, chemical peels, IPL, Q-switched ruby laser, autologous fat transplantation, combinations of fat grafting and blepharoplasties, fillers Riehl melanosis Brown-grey colour Typically preceded by mild erythema and pruritus, followed by a diffuse-to-reticulated hyperpigmentation Favours sites of application of contactants, especially cosmetics Complete avoidance of the suspected allergen and allergen-free soaps and cosmetics Sun-protective measures, skin-lightening agents and chemical peels Melasma Exogenous ochronosis Acanthosis nigricans Dermatosis papulosa nigra Naevus of Ota Hori naevi Ephelides Lentigines Lichen planus pigmentosus Erythema dyschromicum perstans Actinic lichen planus Symmetric, centrofacial distribution of light to dark brown patches with irregular borders History of exacerbation with pregnancy, hormonal therapy such as oral contraceptives, and intense sun exposure History of hydroquinone application Banana-shaped, yellow-brown deposits in the dermis Symmetric, hyperpigmented, velvety plaques on the neck and axillae History of diabetes and/or obesity 1- to 5-mm pigmented papules that are distributed bilaterally across the malar eminences, forehead Blue-grey confluence of individual macules varying from pinhead-sized to several millimetres in diameter Distribution of the first two branches of the trigeminal nerve Onset in infancy or puberty Asians, primarily Chinese and Japanese, women aged years Blue-grey to grey-brown macules primarily on the zygomatic area and less often on the forehead, temples, upper eyelids, and root and alae of the nose 1 3-mm well-demarcated hyperpigmented macules that are round, oval or irregular in shape 3-mm to 2-cm well-circumscribed, round, oval or irregularly shaped macules or patches that vary in colour from tan to dark brown Oval or irregularly shaped grey-brown to brown macules and patches in sun-exposed areas Grey to blue-brown lesions Inflammatory phase with rim of erythema Distribution also includes nonsun-exposed areas Fine scale overlying violaceous lesions Photodistributed Combination approach with strict sun protection, cosmetic camouflage, skinlightening agents, chemical peels and laser therapy Dermabrasion, CO 2 laser, glycolic acid peelings and Q-switched laser Keratolytics, skin-lightening agents, calcipotriol, urea and salicylic acid Snip excision, curettage, electrodesiccation, light cryotherapy and laser destruction Q-switched ruby, alexandrite and Nd:YAG lasers Q-switched ruby, alexandrite and Nd:YAG lasers, cryotherapy Sun-protective measures, skin-lightening agents, cryotherapy and laser surgery Sun-protective measures, skin-lightening agents, cryotherapy and laser surgery Topical steroids, immunomodulators and skin-lightening agents Oral corticosteroids, antibiotics (e.g. doxycycline), antimalarials, isoniazid, griseofulvin and UV light therapy have produced variable results Successful treatment with dapsone and clofazimine has been reported in small series Topical and intralesional corticosteroids, antimalarials (e.g. hydroxychloroquine), acitretin and ciclosporin

4 44 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu Table 1 (continued) Disease Distinguishing features Treatment Erythromelanosis follicularis faciei et colli Post-chikungunya pigmentation Well-demarcated erythema, hyperpigmentation and follicular papules Small macules of brown-black pigmentation or slate-like pigmentation of the centrofacial area History of fever, morbilliform skin eruption and polyarthritis Topical and systemic retinoids, hydroquinone Conservative and symptomatic treatment IPL, intense pulsed light; UV, ultraviolet. Fig 1. Postinflammatory hyperpigmentation secondary to pseudofolliculitis barbae: multiple, small, brown, coalescing macules on the beard area. Fig 2. Maturational dyschromia: hyperpigmented, ill-defined patches over the lateral zygoma in a middle-aged African-American woman. chromia may be misdiagnosed as melasma, acanthosis nigricans or PIH. This is a diagnosis of exclusion and any type of allergic contact dermatitis or photoallergic dermatitis should be ruled out. Treatment options include sunscreen, skinlightening agents, antioxidants, microdermabrasion and/or chemical peels. Fig 3. Secondary periorbital hyperpigmentation: hyperpigmented brown patches on the periorbital area. Periorbital hyperpigmentation Periorbital hyperpigmentation, also referred to as idiopathic cutaneous hyperchromia of the orbital region (ICHOR), periorbital melanosis, dark circles or infraorbital pigmentation, is more frequently observed in the skin of colour population and can be of primary or secondary aetiology. 20 The cause of secondary periorbital hyperpigmentation often has a multifactorial pathogenesis including genetic or constitutional pigmentation, dermal melanocytosis, PIH secondary to atopic and/or allergic contact dermatitis, periorbital oedema, excessive subcutaneous vascularity and shadowing due to skin laxity and tear trough associated with ageing (Fig. 3). 20,21 Excessive sun exposure, drugs, hormonal causes and extension of pigmentary demarcation lines have also been considered to be contributory. 20,22 ICHOR is characterized by bilateral darkening of the orbital skin and eyelid, which is not secondary to systemic or local disease. 20 In a study by Ranu et al. 15 on 200 patients with periorbital hyperpigmentation, possible causes were delineated according to history, physical examination and assessment by dermatologists measuring with a Mexameter â (Courage Khazaka Electronics, Cologne, Germany). They found the commonest forms to be the vascular type (418%) characterized by the presence of erythema involving inner aspects of lower eyelids with prominent capillaries/telangiectasia or presence of bluish discoloration due to visible blue veins; constitutional form (386%) characterized by the presence of brown-black hyperpigmentation of the lower eyelid skin along the shape of orbital rim; PIH (12%); and shadow

5 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 45 effects (114%) due to an overhanging tarsal muscle or deep tear trough. 15 Other causes included skin laxity, dry skin, hormonal disturbances, nutritional deficiencies and other chronic illnesses. 15 Verschoore et al. 23 confirmed that not only melanin deposits but also blood stasis may play a role in the pathogenesis of ICHOR. Regarding the localization of the pigmentation, earlier studies by Watanabe et al. and Malakar et al. examined skin biopsies and found the presence of dermal melanocytosis and melanin pigment in upper dermal macrophages, respectively, partially explaining the recalcitrance of this condition to several treatments. 22,24 Skin-lightening creams, chemical peels, intense pulsed light (IPL), Q-switched ruby laser, autologous fat transplantation, combinations of fat grafting and blepharoplasties as well as fillers have all been tried, but none have provided long-term satisfactory treatment. 15 Riehl melanosis Riehl melanosis, or pigmented contact dermatitis, is characterized by a brown-grey colour secondary to dermal melanin deposits. It favours sites of application of contactants, especially cosmetics. Cases are typically preceded by mild erythema and pruritus, followed by a diffuse-to-reticulated hyperpigmentation. Pigmentation varies, often dependent upon the causal agent. It can be brown or brown-grey, and can also have red and blue hues. Diagnosis is assisted with closed patch testing to standard series, cosmetic series, fragrance series and patients personal products. Photopatch testing can also be considered. When results are equivocal or negative, the provocative use test or repeated open application test can be administered. 24 Treatment involves complete avoidance of the suspected allergen. Sun-protective measures, skin-lightening agents and chemical peels can hasten resolution of pigmentation changes. A rarer aetiology of facial hyperpigmentation and probably a variant of Riehl melanosis is termed erythrose peribuccale pigmentaire de Brocq. It is most likely caused by photodynamic substances in cosmetics. It is characterized by diffuse, symmetric red-brown pigmentation around the mouth with sparing of the vermillion border and may extend to the forehead, temples and angles of the jaw. 25 Pigmentation will persist unless the cause is eliminated. A similar hyperpigmentation has been reported in patients with subsiding perioral dermatitis secondary to topical steroids. 25 Melasma Melasma is an acquired form of hyperpigmentation that is seen most commonly on the face. It is a common disorder of hyperpigmentation affecting millions worldwide. It predominantly affects Fitzpatrick skin phototypes III and IV, 26 and at least 90% of those affected are women. The exact pathogenesis is unknown; however, it is hypothesized that rather than an increase in melanocytes, melasma may be caused by the presence of more biologically active melanocytes in the affected Fig 4. Melasma: light brown patch with irregular borders over the malar eminence in a middle-aged Hispanic woman. skin. 26 Following exposure to UV irradiation, the melanocytes produce increased amounts of melanin compared with uninvolved skin. Exacerbating factors include pregnancy, hormonal therapy, such as oral contraceptives, and intense sun exposure. Sun exposure exacerbates melasma, probably because of the UV-induced upregulation of melanocyte-stimulating cytokines. Clinically, there are light to dark brown patches with irregular borders most commonly distributed symmetrically on the centrofacial, malar and mandibular regions and can also be on the forearms (Fig. 4). Depending on the location of melanin, melasma can be differentiated into different types. In the epidermal type, the pigment is brown and margins are geographical and more well-defined, whereas, in the dermal type, pigment is of a more grey-brown quality and margins are poorly defined. Mixed type occurs when there is melanin in both the epidermis and dermis, and the term indeterminate type may be used when it is difficult to classify even with the assistance of Wood s light. 25 The differential diagnosis includes PIH, solar lentigines, acanthosis nigricans, and other more rare pigmentary disorders including exogenous ochronosis, lichen planus pigmentosus (LPP) and erythema dyschromicum perstans (EDP). Treatment includes a combination approach with strict sun protection, cosmetic camouflage, topical lightening agents, chemical peels and laser therapy. Firstline therapy often includes nondestructive modalities including broad-spectrum photoprotection and topical compounds that affect the pigment production pathway. Second-line therapy consists of the addition of chemical peels, although these must be used cautiously so as not to induce further postinflammatory changes. Laser and light therapies are promising; however, like chemical peeling agents, carry the risk of PIH. Lastly, for women who note the onset of melasma after beginning oral contraceptives, the medication should be stopped if possible. 26 Exogenous ochronosis Ochronosis appears grossly as blue-black pigment and refers to deposition of polymerized homogentisic acid in collagencontaining structures. Exogenous ochronosis occurs when foreign substances cause homogentisic acid to be deposited in the dermis, causing macular and papular hyperpigmentation.

6 46 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu Fig 5. Exogenous ochronosis: bluish-grey discoloration overlying a pink hue on the zygomatic arch. It is a rare disease, characterized by an asymptomatic hyperpigmentation of the face, sides and back of the neck, back and extensor surfaces (Fig. 5). 27 It is clinically and histologically similar to endogenous ochronosis, also known as alkaptonuria; however, it exhibits no systemic effects and is not an inherited disorder. It has been associated with the use of products containing hydroquinone, resorcinol, phenol, mercury and/or picric acid. It is relatively uncommon within the U.S.A. and is more prevalent in Africa. According to a 2007 literature review, 28 there were 789 cases of exogenous ochronosis reported worldwide, only 22 of these were reported from the U.S.A. The aetiology for this phenomenon remain elusive, but could be a result of the use of skin-care products containing resorcinol in combination with hydroquinone or use of hydroquinone in a hydroalcoholic lotion. In both endogenous and exogenous ochronosis, a microscopic deposition of ochrecoloured pigment is found in the dermis. Exogenous ochronosis often needs histological confirmation as it can easily be confused with PIH, pigmented contact dermatitis and melasma. Treatment is difficult. Although not uniform, satisfactory results have been described with dermabrasion, CO 2 laser, glycolic acid peels and Q-switched laser. 27,29,30 Fig 6. Dermatosis papulosa nigra: 1 2-mm brown discrete papules over the malar eminences in an older African-American woman. Dermatosis papulosa nigra and seborrhoeic keratoses Dermatosis papulosa nigra (DPN) is a common manifestation diagnosed primarily in African-American, Afro-Caribbean and sub-saharan African black patients; however, it is also seen in other races. The cause and pathogenesis is unknown. DPN tends to have an earlier age of onset than that of seborrhoeic keratoses, but otherwise is similar and considered a variant of seborrhoeic keratosis. DPN presents as 1- to 5-mm pigmented papules that are distributed bilaterally across the malar eminences, forehead and, less often, on the neck, chest and back (Fig. 6). They appear during adolescence and increase in size and number over time, peaking in the sixth decade. Usually the lesions are asymptomatic but can occasionally be pruritic or irritated. The differential diagnosis includes seborrhoeic keratoses, acrochordons, melanocytic naevi, lentigines, verrucae and other adnexal tumours. Treatment is generally performed for cosmetic purposes and should be exercised with great care given the risks of dyspigmentation. Modalities include snip excision, curettage, electrodesiccation, light cryotherapy and laser destruction. Acanthosis nigricans Acanthosis nigricans is characterized by hyperpigmented, velvety plaques often in a symmetric distribution. Although most commonly appearing on the intertriginous areas of the axilla, groin and posterior neck, acanthosis nigricans may occur in almost any location including the face. Patients typically present with a darkening and thickening of the skin. Acanthosis nigricans is commonly associated with insulin resistance and obesity, and it is more common in Hispanic and black people. No treatment of choice exists for acanthosis nigricans. The goal of therapy is to correct the underlying disease process. Topical medications that have been effective in some cases of acanthosis nigricans include keratolytics (e.g. topical tretinoin 005%, ammonium lactate 12% cream) and triple-combination depigmenting cream (tretinoin 005%, hydroquinone 4%, fluocinolone acetonide 001%) nightly with daily sunscreen. 31 Calcipotriol, podophyllin, urea and salicylic acid have also been reported with variable results. 32 Naevus of Ota Although naevus of Ota has been documented in all skin types, it occurs predominantly in more darkly pigmented individuals, especially in Asian and black people. The lesions occur during infancy, with the majority presenting at birth, and also around puberty. Onset between 1 and 11 years of age and after 20 years of age is unusual. Naevus of Ota is characterized by a blue-grey confluence of individual macules varying from pinhead-sized to several millimetres in diameter. The overall appearance is that of an irregularly demarcated, mottled patch. Size varies from a few centimetres to extensive unilateral and even occasional bilateral involvement. It favours the distribution of the first two branches of the trigeminal nerve, and the most common sites of involvement are the periorbital area, temple, forehead, malar area, earlobe, pre- and retroauricular regions, nose and conjunctivae. Seen in about two-thirds of patients, a characteristic feature is the involvement of the ipsilateral

7 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 47 sclera. Naevus of Ota persists for life and has been treated successfully by Q-switched ruby, alexandrite and Nd:YAG lasers. 33,34 Hori naevi Hori naevi, or acquired bilateral naevus of Ota-like macules, are a common dermal melanocytic hyperpigmentation in Asians, primarily Chinese and Japanese women from 20 to 70 years of age. They are characterized by blue-grey to greybrown macules primarily on the zygomatic area and less often on the forehead, temples, upper eyelids, and root and alae of the nose 35 (Fig. 7). The eye and oral mucosa are not involved. Hori naevi may be misdiagnosed as melasma, lentigines or ephelides. Treatment modalities including cryotherapy, various Q-switched lasers including a combination of a 532-nm Q-switched Nd:YAG laser (QSNY) followed by a 1064-nm QSNY, or combined use of a scanned CO 2 laser or IPL with a Q-switched ruby laser, have been introduced with various clinical outcomes. 36,37 Ephelides and lentigines Ephelides and lentigines are a common manifestation of sun exposure in white patients and less so in those with skin of colour. Ephelides, or freckles, are the result of increased photoinduced melanogenesis and transport of an increased number of fully melanized melanosomes from melanocytes to keratinocytes. Ephelides occur on sun-exposed areas of the body, particularly the face, dorsal hands and upper trunk. They are 1 3-mm well-demarcated, hyperpigmented macules that are round, oval or irregular in shape. They may increase in number and distribution and show a tendency for confluence, but they can fade over time with ageing. Ephelides are benign and show no propensity for malignant transformation. 38 Some ephelides may represent a subtype of solar lentigo. 39 Solar lentigines are found in 90% of the white population aged > 60 years, and their incidence increases with advancing age. 40 Lentigines are more common in white subjects, but also occur in Asians. Inherited patterned lentiginosis favours more lightly pigmented African-Americans, including those with mixed American Indian heritage. Solar lentigines are 3 to 2-cm well-circumscribed, round, oval or irregularly shaped macules or patches that vary in colour from tan to dark brown. They occur on sun-exposed areas, predominantly the dorsal aspects of hands and forearms, face, upper chest and back. Treatment options for ephelides and lentigines include sunprotective measures, skin-lightening agents, cryotherapy and laser surgery. Erythema dyschromicum perstans EDP, or ashy dermatosis, is an asymptomatic, slowly progressive eruption characterized by dermal pigmentation in circumscribed areas. 41 The majority of patients afflicted with this disorder are from Latin America. There is no gender predilection, and EDP usually presents during the second to third decade of life. The aetiology of EDP is unknown, although it has been postulated that a cell-mediated immune reaction to an ingestant, contact or microorganism underlies the areas of pigmentary incontinence. 18,41 There have been reports of EDP development in association with oral ingestion of medications (e.g. benzodiazepines, penicillin), ammonium nitrate and X-ray contrast media; exposure to pesticides or toxins; endocrinopathies; and whipworm and human immunodeficiency virus infections. 18 It has also been postulated that the HLA-DR4 allele may represent a risk factor for EDP in Mexican patients. Clinically, EDP presents as slate-grey to blue-brown oval, circular or irregularly shaped macules and patches that gradually develop in a symmetric distribution (Fig. 8). The long axis of lesions may follow skin cleavage lines. In earlier stages, lesions may have a thin, raised and erythematous border. Lesions typically involve the trunk with spread to the neck, upper extremities and, sometimes, the face. Although usually asymptomatic, EDP may be mildly pruritic. EDP can be difficult to diagnosis and may be confused with other entities including LPP, lichenoid drug eruption, infectious diseases (e.g. leprosy and pinta), and other forms of dermal PIH. EDP Fig 7. Hori naevi: small discrete greyish-brown macules over the malar eminence in an Asian woman. Fig 8. Erythema dyschromicum perstans: multiple, ill-defined, circular, grey-brown patches on the neck.

8 48 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu is very difficult to treat, and there is no consistently effective treatment. Oral corticosteroids, antibiotics (e.g. doxycycline), antimalarials, isoniazid, griseofulvin and UV radiation therapy have produced variable results. Successful treatment with dapsone and clofazimine has been reported in small series. Topical therapies with corticosteroids and hydroquinone are generally of no benefit. The disease progresses slowly and usually does not regress in adults. Lichen planus pigmentosus LPP is an uncommon variant of lichen planus that favours skin phototypes III V. It generally affects young to middleaged adults, especially those from India, Latin America and the Middle East. Clinically, it presents as oval or irregularly shaped grey-brown to brown macules and patches in sunexposed areas, including the forehead, temples and neck, or intertriginous areas (Fig. 9). Lesions are symmetric in the majority; however, they can present in a unilateral, linear fashion. It is typically asymptomatic, but some do describe mild pruritus and/or burning. In one series of 124 patients with LPP, 19 were also noted to have typical lesions of lichen planus. 42 The aetiology for LPP is unknown. Photodistribution suggests that UV radiation may play a pathogenic role. Also, topical application of mustard oil which contains a potential photosensitizer, allyl isothiocyanate, and also amla oil have been proposed as possible inciting agents. 42 The differential diagnosis includes lichen planus, EDP, melasma, lichenoid drug eruptions and PIH. Of note, in contrast to EDP, an erythematous border of early lesions is not a feature of LPP. LPP is a chronic disorder with exacerbations and remissions. Treatment is similar to EDP and LP if lesions typical of LP are found. Options include topical steroids, immunomodulators and skin-lightening agents. In one uncontrolled study, lightening of the pigmentation occurred in 54% (seven of 13) of patients treated with topical tacrolimus for weeks. 43 In addition, in a recent case report, a combination of low-fluence 1064 nm QSNY with topical tacrolimus was reported to be successful. 44 Actinic lichen planus Actinic lichen planus (ALP) represents a rare photodistributed variant of lichen planus and has also been reported under the names of lichen planus actinicus, lichen planus subtropicus, lichen planus tropicus and lichenoid melanodermatitis. It has been observed worldwide; however, the majority of reported patients have been from Middle Eastern countries. 45,46 It typically occurs in young adults and/or children with no gender predilection. The lesions usually consist of red-brown plaques with an annular configuration, but melasma-like hyperpigmented patches have been observed. 18 Lesions are typically photodistributed involving areas of the forehead, face and dorsal surfaces of the upper extremities and neck. Lesions typically appear and/or are exacerbated during the summer months and may improve spontaneously in the winter. The differential diagnosis of ALP includes photosensitive lichenoid drug eruptions, discoid lupus erythematosus, actinic prurigo, fixed drug eruption and polymorphous light eruption. Treatment includes sun-protective measures. Various therapies have been tried in ALP with variable outcomes, including topical and intralesional corticosteroids, antimalarials (e.g. hydroxychloroquine), acitretin and ciclosporin. 45,47 Other aetiologies of facial hyperpigmentation Erythromelanosis folliculis faciei et colli Erythromelanosis follicularis faciei et colli (EFFC) is a rare aetiology of facial hyperpigmentation with fewer than 50 reported cases in the literature, mostly from Japan. 25,48 It is characterized by well-demarcated erythema, hyperpigmentation and follicular papules. It mainly affects young and middle-aged men with onset in adolescence but can also be seen in female subjects. The cause is unknown. Clinically, EFFC manifests as gradually progressive reddish-brown pigmentation and telangiectasias surmounted with small follicular papules from which vellus, but not terminal hairs, are lost. 25 The pigmentation involves the periauricular areas and sometimes extends to the sides of the neck. Often patients have keratosis pilaris lesions on the trunk, with no history of related disorders or family history of atopy. Treatment has included isotretinoin, topical retinoids and hydroquinone. Although clinical regression is difficult to achieve and relapse is common, lesions have been noted to respond to treatment. 48 Post-chikungunya pigmentation Fig 9. Lichen planus pigmentosus: ill-defined, reticulated, brown-grey patches on the neck. Post-chikungunya pigmentation is a rare aetiology of facial pigmentation noted in India since Chikungunya fever is a febrile, mosquito-borne (Aedes aegypti and Aedes albopictus), viral illness, first reported in Tanzania and thereafter epidemics

9 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 49 in several countries. All age groups have been affected. Clinically, an asymptomatic, brownish-black pigmentation in the form of freckle-like macules or, less commonly, slate pigmentation can be seen. The pigmentation generally involves the centrofacial area. Other patterns of pigmentation that have been observed include melasma-like pigmentation over the face, periorbital melanosis, and a flagellate pattern of pigmentation on the face and extremities. 25,49 Lesions may persist for 3 6 months after the infection. Pigmentation changes were found to be the most common cutaneous finding (42%), followed by a maculopapular eruption (33%) and intertriginous aphthous-like ulcers (214%). 49 The exact cause of cutaneous manifestations is not known. Biopsy from hyperpigmented lesions shows an intact basal layer with diffuse hypermelanosis of the entire epidermis, suggesting an increased intraepidermal melanin dispersion and retention from the virus. 25,49 All patients responded well to symptomatic, conservative treatment. 49 Treatment of facial hyperpigmentation Facial hyperpigmentation can cause significant cosmetic disfigurement with subsequent emotional impact. 25,50,51 Treatment continues to be challenging as there is no universally effective therapy, and existing agents have varying degrees of efficacy. Because the majority of reports regarding treatment consist of small series of patients and anecdotes, it is difficult to evaluate the efficacy of different forms of therapy. In addition, although multiple options do currently exist, some therapies have come under increasing scrutiny, underscoring the need Table 2 Skin-lightening agents. Adapted from [52]. Mechanism of action Tyrosinase inhibition Reduction in melanosome transfer Interaction with copper Stimulation of keratinocyte turnover Inhibition of melanosome maturation Inhibition of protease-activated receptor 2 Oxidation and breakdown of melanin Compound Arbutin Azelaic acid DeoxyArbutin Glycolic acid Hydroquinone Liquorice extract Mequinol N-Acetylglucosamine N-Acetyl-4-S-cysteaminylphenol Niacinamide Retinoids Soybean trypsin inhibitor Ascorbic acid Kojic acid Glycolic acid Retinoids Arbutin DeoxyArbutin Soybean trypsin inhibitor Lignin peroxidase for research into pathogenesis and treatment. Overall, treatment includes removal of provoking factors, photoprotection, and forms of active pigment reduction with either topical formulations or physical modalities (Table 2). General instructions Those with skin types IV VI need special considerations in preventing and treating various aetiologies of facial hyperpigmentation. Peak hours of sunlight (between 11:00 and 16:00 h) should be avoided in addition to seeking shade and wearing protective clothing (e.g. broad-brimmed hats and long-sleeved shirts). Avoiding provoking triggers is necessary for many types of facial hyperpigmentation including melasma, pigmented contact dermatitis and PIH. If melasma has been induced by the use of oral contraceptives, discontinuation should be considered. Sunscreens Several studies have shown that light from both the UV and visible spectrum can induce pigmentary changes in the skin. 52,53 Redistribution and oxidation of pre-existing melanin cause immediate pigment darkening and occurs after low-dose UVA exposure and usually fades after 2 h. 53,54 After high doses of UVA exposure, persistent pigment darkening may develop, lasting up to 24 h. Both UVA and UVB exposure can cause melanin synthesis resulting in delayed tanning. Given clinical experience and available data, broad-spectrum UVA and UVB protective sunscreen with an SPF of at least 30 ideally including a physical block (e.g. titanium dioxide or zinc oxide) should be used for prevention of facial hyperpigmentation. Vitamin D is essential for bone health, and as cutaneous synthesis is a well-known source, it is important to counsel patients properly when advocating strict sun protection. Darker-skinned patients have an inherently lower vitamin D level and those that live in environments that do not have regular sun exposure and/or are adhering to strict sun-protective measures may require supplementation and monitoring. The National Academy of Sciences Institute of Medicine recommended dietary allowance (RDA) for vitamin D is 400 international units (IU) for infants/children aged 0 1 years, 600 IU for those aged 1 70 years and 800 IU for those aged 71 years. Sources include fortified milk, cheese, yogurt and cereal and also oily fish (i.e. salmon and tuna). Fortified foods are rich in both vitamin D and calcium and maintain phosphate levels, which are also needed for bone health. Cosmetic camouflage Physical blocking opaque sunscreens have the dual benefit of camouflaging facial hyperpigmentation and preventing photoinduced darkening. Many of these physical blockers now come in tinted blends to help with camouflaging. In addition, many patients find that the use of make-up helps even out skin tone. Several available brands that provide heavy coverage include

10 50 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu Dermablend â (Vichy Laboratories, Paris, France), Cover FX â (Cover FX Skin Care, Toronto, Ontario, Canada), Covermark/ CM Beauty â (CM Beauty, Northvale, NJ, U.S.A.). 52 Topical treatments Topical treatments for disorders of facial hyperpigmentation are aimed at disrupting the enzymatic processes of pigment production within the melanocytes. In the process of melanin production, tyrosinase is the rate-limiting enzyme converting L-tyrosinase to L-3,4-dihydroxyphenlalanine (L-DOPA). L- DOPA is a required cofactor, and copper is also an important molecule that interacts at tyrosinase s active site. Many compounds target these molecules leading to a decrease in melanization. Hydroquinone Hydroquinone (1,4-dihydroxybenzene) is the gold standard for the treatment of facial hyperpigmentation and has been used for more than 50 years. It is thought to act by inhibition of tyrosinase thus reducing the formation and melanization of melanosomes. This also leads to the destruction of melanosomes and possibly even the inhibition of DNA and RNA synthesis. 55,56 Being an oxidizing agent, hydroquinone changes from white to brown at which time it needs to be discarded as it is ineffective. 57 The efficacy of hydroquinone depends on several factors including location of pigment with epidermal pigmentation responding better than dermal, concentration of hydroquinone and vehicle of administration, hydroalcoholic solution being the most effective. 25 Used in concentrations of 2 5%, the response in melasma becomes evident after 5 7 weeks and therapy may be continued for 3 12 months. 25,50 Ennes et al. found that 38% of patients with melasma treated with 4% hydroquinone had a complete response vs. only 8% treated with placebo. 58 In a nonrandomized trial, 4% hydroquinone and broad-spectrum sunscreen was shown to be efficacious in the treatment of melasma, with 895% of subjects showing good to excellent responses. 59 Adverse reactions to hydroquinone are dose and duration dependent. Reactions include asymptomatic transient erythema, irritation, confetti-like depigmentation with higher concentrations and exogenous ochronosis. Uncontrolled access to high concentrations of hydroquinone and/or overuse can increase the risk of adverse events. Over the past few years, concern has been growing over the use of topical hydroquinone. One concern is the potential risks from benzene derivatives after hepatic metabolism, which are proposed to cause bone marrow toxicity and exert antiapoptotic effects. 60 Topical hydroquinone, however, bypasses the liver initially, and the major route of metabolism is via water soluble, renally excreted molecules. 52,60 In a review of hydroquinone safety issues, Nordlund et al. maintained that there does not appear to be more than a theoretical risk of malignancy and very low risk of other side-effects, including exogenous ochronosis, when using prescription topical preparations of hydroquinone under physician supervision. 61 In addition, there have been no reports to date of skin or internal organ malignancies occurring in humans as a result of topical hydroquinone application. 61 Azelaic acid Azelaic acid is a 9-carbon dicarboxylic acid derived from Pityrosporum ovale, which is antiproliferative and cytotoxic to melanocytes. It acts as a weak, reversible, competitive inhibitor of tyrosinase. Another possible mechanism of action includes decreased free radical formation. It has been used in the treatment of both melasma and PIH. In patients with melasma, 20% azelaic acid was found to be as effective as 4% and superior to 2% hydroquinone, but without side-effects. 62 Overall, azelaic acid is well tolerated with the most commonly reported side-effects including pruritus, mild erythema, scaling and burning. Retinoids Retinoids reduce hyperpigmentation through multiple mechanisms including promoting loss of melanin through the stimulation of keratinocyte turnover, reducing melanosome transfer and allowing for greater penetration of other active ingredients. 63 Retinoids are thought to inhibit tyrosinase transcription, interrupt melanin synthesis and inhibit tyrosinaserelated proteins 1 and Available retinoids (retinoic acid, tretinoin, adapalene, tazarotene) have been used to treat melasma and PIH, either as monotherapy or combined with other agents including hydroquinone and topical steroids. As monotherapy, higher percentages of retinoic acid (01%) have been found to be more effective for melasma than lower percentages (005%, 0025%), however, also more irritating. 64 In a randomized controlled trial, 01% tretinoin was found to be more effective than the vehicle for treating patients with melasma. 65 Importantly, it took longer, 24 weeks, in these studies to see significant improvement. Adapalene (01%) has been found to be as efficacious as tretinoin (005%) with significantly less irritation in the treatment of melasma. 66 Once-daily application of 01% tazarotene cream was shown to be effective against PIH, achieving significantly greater reductions compared with vehicle in overall disease severity and in the intensity and area of hyperpigmentation within 18 weeks. 67 In a study comparing 01% tazarotene cream and 03% adapalene gel, both were found to be effective and well tolerated in the treatment of PIH; however, tazarotene was more effective. 68 Topical 005% isotretinoin gel applied daily with SPF 28 sunscreen has been evaluated in the treatment of melasma in Thai patients; however, this application did not show increased efficacy vs. vehicle and sunscreen alone. 69 Retinoids have been found to be effective when combined with other agents including but not limited to hydroquinone, lactic acid and ascorbic acid. Irritation is the most common side-effect and may even cause hyperpigmentation so should be used cautiously.

11 Facial hyperpigmentation, N.A. Vashi and R.V. Kundu 51 Mequinol Mequinol (4-hydroxyanisole) is a derivative of hydroquinone and acts as a competitive inhibitor of tyrosinase, reducing the formation of melanin precursors. For the treatment of solar lentigines, a topical combination of 2% mequinol and 001% tretinoin solution was well tolerated and superior to either active component and vehicle, 70 and in another study, it was found to be superior to hydroquinone 3% for solar lentigines on the forearm and similar efficacy for facial lesions. 71 This combination has also resulted in complete clearance in four of five men with melasma at 12 weeks with all patients maintaining improvement at 16 weeks. 72 Treatment-related adverse events for combination productions include erythema, burning/stinging/tingling, desquamation, pruritus, hypopigmentation and halo hypopigmentation. Symptomatic sideeffects were found to decrease when used with sunscreen of SPF 25 or greater. 73 Although efficacious in combination products, controlled clinical trials are still needed to establish the place of mequinol in the management of facial hyperpigmentation. Kojic acid Kojic acid is produced by Aspergillus oryzae and Penicillium spp. 74 It inhibits the production of free tyrosinase by inhibiting tyrosinase through chelation of copper at the enzyme s active site. The agent is usually available over the counter in a 2% concentration. When used alone, 1 4% formulations are only modestly efficacious; however, it can also be used in combination formulations. Studies have found mixed results. For melasma, in one split-face trial, a gel containing glycolic acid, hydroquinone and kojic acid showed more improvement (60%) in patients than a gel that contained only glycolic acid and hydroquinone (475%). 75 In another split-face trial comparing a combination glycolic acid and kojic acid preparation with a glycolic acid and hydroquinone preparation, authors found no statistically significant difference in clinical efficacy. 76 Important to note is that kojic acid is a known sensitizer and may cause contact dermatitis and erythema. 77 Ascorbic acid Ascorbic acid, also known as vitamin C, has antioxidant properties and reduces melanogenesis by interacting with copper at the active site of tyrosinase and by reducing dopaquinone by blocking dihydrochinindol-2-carboxyl acid oxidation. 52,77 In a randomized trial, patients with melasma found greater subjective improvement to one side of the face treated with 4% hydroquinone cream (93%) than the other side of the face treated with 5% ascorbic acid cream (625%). 78 However, ascorbic acid had a better safety profile causing significantly less irritation than hydroquinone; therefore, it may be a useful adjunctive treatment in those unable to tolerate hydroquinone. In another study, a 25% L-ascorbic acid formulated with a penetration enhancer was found to improve melasma significantly. 79 Because of its instability in aqueous solution, esters like magnesium ascorbyl-2-phosphate (MAP) with similar properties have been used. 80 MAP was found to reduce pigmentation significantly in 19 of 34 patients with melasma and senile freckles but only in three of 25 patients with normal skin. 81 Ascorbic acid can be used alone or in combination therapy. Overall, this molecule is rapidly oxidized, highly unstable and does not work well alone; it is, therefore, usually combined with other agents such as liquorice extracts and soy to increase efficacy. Liquorice derivatives Liquorice is the root of the perennial herb, Glycyrrhiza glabra. Liquorice extract has anti-inflammatory properties and contains glabridin, which inhibits tyrosinase in vitro. 82 Other active ingredients are liquiritin and isoliquiritin, which, respectively, disperse melanin and contain flavonoids. In a split-face trial, a 20% liquiritin cream was found to be effective at 4 weeks in the treatment of epidermal melasma. 83 The use of 1 g per day for 4 weeks is often used before any benefit is seen. 77 Soy Soybean trypsin inhibitor reversibly inhibits the protease-activated receptor-2 pathway that is needed for melanosome transfer. 84 Inhibition of this pathway caused a dose-dependent loss of pigmentation by as early as 4 weeks at the highest tested dose. 85 Additional work on this pathway has shown that soymilk and the soybean-derived serine protease inhibitors can inhibit both baseline and UVB-induced pigmentation in vitro. 86 In a multiagent comparative trial, soy extract was shown to have a modest effect in lightening solar lentigines. 87 Arbutin/deoxyArbutin Arbutin is the naturally occurring b-d-glucopyranoside derivative of hydroquinone that is derived from the bearberry plant, and deoxyarbutin is a dehydroxylated derivative of arbutin. Arbutin is hydrolyzed in the skin to hydroquinone and produces skin lightening by direct, dose-dependent inhibition of tyrosinase. 88 The synthetic deoxyarbutin is a more potent tyrosinase inhibitor, and in guinea pig and human tests has been shown to be more rapidly effective. 89 Although good controlled clinical trials are lacking, initial in vitro and in vivo experiments have demonstrated its safety and efficacy in hypermelanotic disorders. 90 It has been used in Japan at concentrations of 3%; of note, at higher concentrations it may cause paradoxical hyperpigmentation. 77 Niacinamide Niacinamide reduces pigmentation by reversibly preventing the transfer of melanosomes from melanocytes to the keratino-