Facial Pigmentation Common Causes and How to Manage THOMAS STEWART Bbiomedsc(Hons), MB BS ROBERT ROSEN MB BS, Mmed, FACD

PEER REVIEWED FEATURE 2 CPD POINTS Facial pigmentation Common causes and how to manage THOMAS STEWART BBioMedSc(Hons), MB BS ROBERT ROSEN MB BS, MMed, FACD

Facial pigmentation may be due to a generalised round 14% of GP consultations are for the management process but most often is localised to the face. of skin diseases.1 Pigmentary disorders represent a large Melasma and actinic damage pigmentation are proportion of diagnoses in dermatological populations.2 common and tend to be bilaterally distributed and Melasma, the most common facial pigmentation world- Awide, may account for up to 10% of new dermatology referrals,3 slowly progressive. Irregularly shaped isolated lesions should be viewed with more caution, and and GPs therefore need to be able to recognise it. biopsy may be required. Treatments include topical Skin pigmentation normally varies according to racial origin and oral medications, peels, intense pulsed light and the amount of sun exposure, and pigmentation disorders are often more troublesome in constitutionally darker skin (‘skin therapy and laser treatment. of colour’). Facial hyperpigmentation manifests as either localised to the face or part of diffuse disease. Pigmentation localised to KEY POINTS the face usually represents a benign condition, although it may be the cause of significant psychological distress because of its • Diagnosis of the type of facial pigmentation can be made high visibility and sociocultural implications (regardless of the on clinical grounds in most cases. nature of the problem, people generally desire uniformity of skin Facial pigmentation is a cause of considerable • colour). Increased facial pigment can, however, herald underlying psychosocial distress for many patients. systemic disease or malignancy. • Melasma, the most common facial hyperpigmentation worldwide, is most prevalent in women and people with Melanin contributes to racial and phenotypic appearance, but constitutionally darker skin. It occurs in approximately also has important roles in protecting from ultraviolet (UV) 25% of women who are pregnant. radiation damage and scavenging of toxins. Several pigment • Hydroquinone-based skin-bleaching preparations remain intensifiers have been identified, the most notable of which are the gold standard for the treatment of melasma. UV radiation and, in the setting of melasma, oestrogen and • Many patients with facial pigmentation can be managed progesterone. The process of pigment intensification is thought in the general practice setting but referral for specialist to involve an increase in pigment production and/or melanocyte management may be required for refractory cases. numbers, usually mediated, at least in part, by the enzyme tyrosinase. Several established treatments target this enzyme, although improved understanding of melanogenesis in recent times has MedicineToday 2016; 17(10): 30-38 seen the emergence of several novel treatment options. This article reviews the causes of hyperpigmentation and Dr Stewart is a Research Fellow, and Dr Rosen is a Dermatologic Surgeon and discusses treatment options for facial pigmentation that can be WHITESHOES911/DEPOSITPHOTOS. MODEL USED FOR ILLUSTRATIVE PURPOSES ONLY. PURPOSES ILLUSTRATIVE FOR USED MODEL WHITESHOES911/DEPOSITPHOTOS.

Managing Director, Southern Suburbs Dermatology, Sydney, NSW. used in general practice. ©

30 MedicineToday ❙ OCTOBER 2016, VOLUME 17, NUMBER 10 Downloaded for personal use only. No other uses permitted without permission. © MedicineToday 2016. Generalised versus localised disease (e.g. Crohn’s disease), and alcohol- 1. COMMON FACIAL PIGMENTATIONS hyperpigmentation ism is known to deplete folic acid stores. Generalised hyperpigmentation may be The endocrinopathies and metabolic • Melasma drug-induced, nutrition-related, have endo- ­disorders most commonly associated with crine or metabolic causes or occur after systemic hyperpigmentation are Addison’s • Postinflammatory inflammation. It can also occur with malig- disease, haemochromatosis and hyper­ • Sun-damaged skin nancies or have genetic causes. Limited thyroidism; although patients may have • Photosensitivity facial pigmentation, the most common associated symptoms or a past medical –– connective tissue disease presentation of localised hyperpigmenta- or family history suggestive of these –– drugs tion, typically is part of several common conditions, pi­ gment changes are often • Naevi and largely benign skin conditions. Solar among their first signs. Postinflammatory –– Ota –– Hori lentigines (freckles), melasma and post­ hyperpigmentation is not a common cause inflammatory hyperpigmentation are some of ‘generalised’ hyperpigmentation. • Fixed macules –– lentigines (solar and other) of the more common facial pigmentations Far less frequently, occult malignancy –– seborrhoeic keratoses (Box 1). such as adreno­corticotrophic hormone (ACTH)-­producing lung carcinomas and Generalised hyperpigmentation metastatic melanomas may cause gener- disease are loss of androgen-stimulated hair, The causes of generalised hyperpigmen- alised hyper­pigmentation. such as pubic and underarm hair. Patients tation are listed in Box 2. Drug-induced Symmetrical distribution is a hallmark with hyperthyroidism may display the Addi- hyperpigmentation may occur with use of of hyperpigmentation caused by systemic sonian pattern of pigmentation but involve- minocycline and hormonal contraceptives. disease. In patients with Addison’s disease, ment of mucous membranes is uncommon Nutrition-related hyperpigmentation may hyperpigmentation is most intense on and darkening of nipples and genital skin is be seen with deficiencies of vitamin B12 light-exposed areas, in skin creases and less striking; the eyelids are occasionally or folate associated with inadequate dietary ­flexures, at sites of friction and on mucous pigmented and some patients show localised intake or gastrointestinal malabsorptive membranes; other associated features of this ‘melasmal’ rather than diffuse pigmentation.

2. CAUSES OF GENERALISED HYPERPIGMENTATION*

Drug and toxins • Inflammatory dermatoses such as • Carcinoid syndrome • Analgesics (NSAIDS) acne, psoriasis • Hyperthyroidism (one of the most • Antiarrhythmics (amiodarone) • Medication use (e.g. hydroquinone, frequent endocrine causes) • Antibiotics (tetracyclines [e.g. tretinoin) • Acanthosis nigricans minocycline], co-trimoxazole) • Postinfective (e.g. tuberculosis, Metabolic • Anticonvulsants (phenytoin) malaria, subacute bacterial endocarditis, HIV) • Chronic renal failure • Antidepressants (imipramine, desipramine) • Ultraviolet light (most frequent • Chronic liver disease • Antimalarial drugs (hydroxychloroquine, postinflammatory cause) • Haemochromatosis (most frequent chloroquine) metabolic cause) • Cytotoxics (bleomycin, busulfan, Nutritional • Porphyria cyclophosphamide, 5-fluorouracil) • Kwashiorkor • Heavy metals (arsenic, bismuth, gold, Malignancy • Pellagra mercury, silver) • Melanoma (rarely) • Scurvy • Hormones (oestrogen, progesterone, • Small cell lung carcinoma (rarely) adrenocorticotrophic hormone) • Vitamin B12/folate deficiency (most frequent nutritional cause) • Psychotropics (phenothiazines Genetic [e.g. chlorpromazine]) • Familial (e.g. periorbital Endocrine hyperpigmentation) Postinflammatory • Pregnancy • Chromosomal (e.g. xeroderma • Allergic dermatitis • Addison’s/Cushing’s disease (one of pigmentosum; dyskeratosis • Autoimmune disorders such as systemic the most frequent endocrine causes) congenital) lupus erythematosus/scleroderma • Phaeochromocytoma • Racial (e.g. naevi of Ota, Ito, Hori) * Causes listed in alphabetical order.

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lentigines appear during childhood (Figure TABLE 1. FITZPATRICK SKIN TYPES 3). Melasma onset spans the reproductive Skin type Skin/hair/eye colour; example ethnicity Characteristics years from 20 to 40 years of age. Cutaneous systemic lupus erythematosus and naevus I White; very fair, red or blonde hair, blue Always burns, never tans of Hori (also known as acquired bilateral eyes, freckles; Celtic naevus of Ota) similarly have broad II White; fair, red or blond hair; blue, Usually burns, tans with ­spectrums of onset, appearing between hazel or green eyes difficulty the ages of 20 and 50 years, and 20 and III Cream white; fair with any eye or hair Sometimes mild burn, gradually 70 years, respectively. Actinic damage and colour (common) tans seborrhoeic keratoses become apparent during the fourth decade of life and usually IV Brown; typical Mediterranean Rarely burns, tans with ease Caucasian skin; Asian increase in number with age.

V Dark brown; mid-eastern skin types, Very rarely burns, tans easily Comorbidities East Indian A specific history should be sought regard- VI Black; Aboriginal and Torres Strait Never burns, tans very easily ing endocrinological and metabolic Islander ­conditions associated with skin hyper­ pigmentation (Table 1). Patients with haemochromatosis have slate • examination grey or brownish-bronze skin, mostly in –– morphology Medication use sun-exposed areas and particularly on the –– distribution. Hormonal contraceptive use commonly face; other associated features include skin triggers melasma in women. Minocycline and nail changes such as hair loss and Fitzpatrick skin type and phenytoin are other recognised causes ­koilonychia (twisted nail plate). Solar lentigines and other hyperpigmen- of facial hyperpigmentation, and other tations due to actinic (solar) damage are parts of the body and mucosa may also be Assessing localised seen predominantly in people with Fitz- involved.6 hyperpigmentation patrick skin types I to III, the predominant Specific lesional characteristics such as Diagnosis of the various facial pigmentations skin types in Australia, whereas melasma colour (e.g. brown, grey, blue-grey) and can be made on clinical grounds in most and postinflammatory hyperpigmentation ­distribution depend on the causative cases. Differential features can be identified are seen mainly in people of skin types III agent. In the case of minocycline-induced using the following diagnostic schematic: to VI (Table 1; Figures 1 and 2).4,5 ­pigmentation, ‘prototype’ minocycline • skin type ­degradation products are chelated with iron • history Onset and duration taken up by macrophages and pigmented –– onset and duration Naevus of Ota (pigmented dermal ‘birth- drug metabolites deposited in the skin. –– comorbidities mark’) exhibits a bimodal onset, present- Minocycline also increases levels of melanin –– medication use ing either at birth or puberty, whereas solar in epidermal and dermal macrophages.

Figure 1. Freckles and an ink spot lentigo (also known as reticulated lentigo; occurs after sunburn in very fair skinned people). Figure 2. Melasma in type V skin.

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the forehead and malar regions. Naevi of Ota are distributed unilaterally (rarely bilaterally) in the skin innervated by the first two branches of the trigeminal nerve, whereas naevi of Hori are bilaterally dis- tributed. Naevi of Ota are most commonly found in people of Asian origin, and are uncommon in Caucasians.

Initial investigations for hyperpigmentation Tests used in the initial investigation of generalised and facial hyperpigmentation are listed in Table 2.

Melasma Figure 3. Naevus of Ota. Melasma, often referred to as ‘chloasma’ Figure 4. Lentigo maligna (preauricular region). or the ‘mask of pregnancy,’ is the most Pigment depth varies dependent on the common facial pigmentation presentation The pathophysiology of melasma is drug, dose, duration of use and patient fac- worldwide, with a reported prevalence of uncertain but an interplay of multiple tors; biopsy may be useful for assessment. about 6 to 9% in a Brazilian population-­ inciting and exacerbating factors has based study.8 Women are affected nine been proposed. Genetic predisposition Morphology times more often than men, and it occurs is suggested by a high reported incidence Facial pigmentation diseases may have in about 25% of pregnant women. People in family members in several s­ tudies. UV macules varying in pigment intensity. with constitutionally darker skin (i.e. Fitz- radiation, oestrogen and progesterone ­Lentigines and melasma characteristically patrick skin types III to VI) are affected induce melanocyte proliferation, migra- produce well-circumscribed lesions, more than people with light skin. tion and melanogenesis independently and whereas actinic damage and solar lentig- Clinically, it is an acquired ­progressive, through upregulation of tyrosinase activity ines typically give a blotchy or speckled nonscaling hypermelanosis of sun-­ (Figure 5).9 Hydroquinone, the mainstay appearance (Figures 1 and 2). Seborrhoeic exposed skin, chiefly affecting the face, of systemic treatment for melasma, and keratoses can sometimes resemble flat more specifically the forehead, cheeks and several other skin-lightening agents target lentigines, but are distinguished by a chin regions. tyrosinase primarily. ­characteristic waxy/scaly veneer. Naevi of Ota lesions sometimes coalesce forming TABLE 2. INITIAL INVESTIGATIONS FOR HYPERPIGMENTATION larger patches (Figure 3). Melanomas such as lentigo maligna are Cohort Clinical suspicion Indicated tests unilateral irregularly shaped lesions, often Generalised Nutritional cause Measurement of levels of serum variegated in colour and architecture and hyperpigmentation vitamin B12 and folic acid best appreciated on dermoscopy (Figure 4). without obvious aetiology Endocrine cause Measurement of levels of serum Timeline to invasion is variable and even electrolytes, thyroid stimulating invasive thin melanomas may evolve hormone, cortisol, adrenocorticotrophic slowly.7 Lesions diagnosed as a melanoma hormone and, possibly, urinary or c­ onsidered a potential melanoma should catecholamines always be biopsied or referred for confocal Metabolic cause Serum liver and kidney function tests, analysis. iron studies

Distribution Localised facial Melanoma e.g. lentigo Punch biopsy, or excisional biopsy hyperpigmentation maligna where possible Lentigines (all types), melasma, photo- where diagnosis is sensitive reactions and actinic elastosis uncertain Postinflammatory Examination for primary cutaneous are most typically found bilaterally on e.g. systemic lupus inflammatory event such as drug erythematosus reaction, connective tissue disease sun- ­exposed areas of the face, particularly

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L-Tyrosine

Tyrosinase

DOPA

Tyrosinase

Dopaquinone

Eumelanin Phaeomelanin (black/brown pigment) (red/yellow pigment)

Figure 5. Tyrosinase-mediated reactions in the melanin production pathway.

Melasma is a chronic condition and recurrence is common, especially after re-exposure to sunlight. Intermittent, long-term topical therapy and strict sun protection are usually necessary to remain in remission. In some patients, areas of hyperpigmen- tation may never completely resolve.

Treatment of facial pigmentation The management of the more common facial pigmentation disorders of melasma, lentigines, actinic damage and naevi are considered here. Although solar lentigines are a more common pigmentary problem than melasma in Australia, they are ­relatively straightforward to treat and so discussion will focus on the treatment of melasma, which remains a therapeutic challenge. All patients with melasma should be counselled about the condition’s natural history and the management goals – ‘control rather than cure’. Treatment options for generalised pigmentation are diverse and aimed at managing its multiple causes, as previously listed, once the cause has been confirmed by investigation.

General measures The first step in managing patients with skin pigmentation is to reduce and/or eliminate any triggers, such as cessation of the hormonal contraceptive in women with melasma. All patients with facial pigmentation should be instructed to apply a broad-spectrum sunscreen (at least SPF 30+) con- taining a physical blocking agent (e.g. zinc oxide), backed by other sun protection measures including wearing a hat and long-sleeved clothing. The appropriate reapplication interval,

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which may be up to two-hourly, should 7 weeks, although treatment can be safely 10 3. EXAMPLES OF COMMERCIALLY be guided by the risk pertaining to sun continued for up to 12 months. Hydro- AVAILABLE COSMETIC CAMOUFLAGE exposure and the nature and level of out- quinone is most commonly used, and PRODUCT BRANDS door activity. potentially best ­utilised in combination Cosmetic camouflage provides photo­ with other agents including retinoids (e.g. • Dermablend (Vichy Laboratories) protection as well as aiding cosmesis; a tretinoin) and corticosteroids (e.g. fluo- • CM Beauty (formerly Covermark) few commercially available products are cinolone) to reduce side effects of each listed in Box 3. When camouflage is not individual ingredient.10 • Microskin (Microskin International worn, sunscreen should be used. Side effects reported as mild and tran- Pty Ltd, Brisbane) sient include irritation, erythema, irritant • Cover FX (Cover FX skin care) Topical therapies or contact dermatitis and halo hypochro- Hydroquinone mia. Rarer longer-term reactions include The main therapy for melasma is the milia and postinflammatory hyper­ epidermal pigmentation in melasma as skin-lightening agent hydroquinone. This pigmentation. Initial concerns about the monotherapy (off label use).12,13 Adapalene ­benzene metabolite exerts multimodal breakdown products of hydroquinone is the first choice because it shares similar effects through competitive inhibition of causing bone marrow toxicity and anti­ efficacy with its peers but is generally bet- tyrosinase-mediated melanin production, apoptotic effects are unsupported by more ter tolerated.13 Tazarotene may offer degradation of melanosomes and inhi­ recent clinical research.11 slightly superior results in postinflamma- bition of nucleic acid synthesis. It is used tory hyperpigmentation (e.g. acne).14 in varying concentrations, with 4% Retinoids Unfortunately, retinoids can take up to appearing to be most advantageous. The acne treatments tretinoin and 24 weeks to show effects so are best used Improvement is usually evident after 5 to adapalene have been shown to reduce in combination with other agents that

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have quicker effects (i.e. hydroquinone plasminogen–plasmin system, interfering Specialist referral is recommended and fluo­cinolone). Retinoid products with the kerat­inocyte–melanocyte for medium and deep chemical peels should be avoided in pregnancy because interaction. like trichloroacetic acid and phenol, of the potential for teratogenicity. TXA is being used in an oral form as respectively. ­limited duration therapy by some derma- Azelaic acid tologists in Australia for melasma that has Dermabrasion Azelaic acid monotherapy has proven value not responded to topical agents (off label Dermabrasion is not popular as a treat- in treating melasma (off label use) and use).10 The most commonly reported side ment for facial pigmentation due to long postinflammatory hyperpigmentation effects are headaches, GI upset and downtimes and poor results. such as that caused by acne. In a rando­ ­hypomenor­ rhoea.­­ Rare instances of throm- mised, double blind study, 20% azelaic boembolism, pulmonary embolus and Light therapies acid was shown to be as effective as hydro­ ­myocardial infarction advocate for a cautious Phototherapy for skin disorders carries an quinone 4% in the treatment of melasma, approach in people with hypercoagulable inherent risk of postinflammatory hyper- but without its side effects.15 In the event of states (e.g. smokers, those who are obesity, pigmentation, and light and lasers should adverse effects, patients might be instructed those with a past history of thrombo­embolic be used with extreme caution. Patients to reduce dosing intervals and/or cease use disease) and those with comorbidities (e.g. must be well versed in the risks. A test temporarily, reintroducing when the effects hypertension) and of advanced age.19 With patch is recommended prior to initiation have resolved. future examination, it may become part of of treatment, especially in patients with the GP’s armamentarium for treating types IV, V or VI skin. Lasers and energy Ascorbic acid ­melasma but at this stage consideration devices are second-line treatment and only Topical ascorbic acid (vitamin C) is ­warrants referral to a dermatologist. considered when topical therapies have modestly effective as monotherapy for not been suitably effective. In Australia, melasma but much less so than hydro­ GPs, specialists, skin clinics and beauti- quinone. Ascorbic acid has a superior cians perform light treatments. safety profile however, and therefore may 'The main therapy for Intense pulsed light therapy. Intense be of use in people who cannot tolerate melasma is the skin-lightening pulsed light (IPL) technology is replacing hydroquinone.16 It is available in many agent hydroquinone.' laser as the standard first-line treatment over-the-counter cosmeceuticals, both as in photodamage. This transition is cred- monotherapy and in combination with ited to improved efficacy coupled with other agents. comparatively less downtime. Lentigines Physical therapies are among the many examples of pig- Combination therapy Chemical peels mented lesions that have been successfully Retinoid, hydroquinone and fluocinolone Chemical peels have variable success in treated. Concomitant use of a Nd:YAG combination therapy produces the best reducing skin pigmentation and multiple (neodymium-doped yttrium aluminium and longest-lasting results of any com- treatments are usually required to achieve ­garnet) laser provides additional benefit mercially available topical agents for the modest results. They are best used in with no additional downtime.22 treatment of melasma.17 A combination ­combination with topical agents such as IPL has also been used adjunctively with skin-bleaching product is marketed as hydroquinone 4%. varied success in melasma; trials have Tri-Luma (hydroquinone 4%, tretinoin Low concentrations of alpha-hydroxy reported almost ­universal recurrence how- 0.05%, fluocinolone acetonide 0.01%) in acids such as glycolic, lactic and salicylic ever, ­perhaps directing best use at disease the USA but is not approved for use in are most commonly used. Glycolic acid refractory to topical therapy alone.23 Broad- Australia. Safety concerns were exagger- (20 to 30%) may be best for solar damage band light (BBL), which utilises a spectrum ated in the early stages of its use, curbing hyperpigmentation and people with types of non­ablative and visible light, has shown interest.18 Tri-Luma can be accessed on I or II skin.20 Salicylic acid (20 to 30%) similar benefits in photo­damage, par­ private prescription through compound- has been shown to be particularly bene- ticularly for lentigines and ­epidermal ing chemists. ficial for melasma and postinflammatory dyspig­mentation. Its effects may be hyperpigmentation in patients with dark ­augmented when used in c­ombination Tranexamic acid skin.21 Patients must be forewarned about with a Er:YAG (erbium-doped yttrium Tranexamic acid (TXA) has been reported the risks of erythema, irritation, burning ­aluminum garnet) laser.21 as a promising potential treatment for and, less commonly, postinflammatory Fractional photothermolysis. Er:YAG and melasma. It is thought to inhibit the hyperpigmentation and scarring. carbon dioxide (CO2) fractional lasers (the

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laser beam is divided into thousands of Conclusion ONLINE CPD JOURNAL PROGRAM microscopic treatment zones that target a Facial pigmentation may be due to a fraction of the skin at a time) are ef­ fective ­generalised process but most often is local- Is melasma more common in for actinic damage­ and lentigines but should ised to the face. The common melasma people with light or dark skin? be considered second line, Er:YAG for and actinic damage pigmentations tend superficial or mild damage and CO2 for to have a bilateral distribution and be deeper photodamage.­ 25 slowly ­progressive. Irregularly shaped Fractional lasers are approved in some ­isolated lesions should be viewed with countries (e.g. the USA) for the treatment more caution, and biopsy may be required of melasma but are not routinely used to exclude melanoma. Treatments include because any short-term improvement is topical and oral medications and physical outweighed by the risk of causing other therapies such as peels, intense pulse light pigment problems. therapy and lasers. MT Other. Q-switched lasers and combined References Er:YAG/CO2 lasers have either never Review your knowledge of this topic shown benefit or have been associated A list of references is included in the website version and earn CPD points by taking part with unsatisfactory adverse effects or of this article (www.medicinetoday.com.au). in MedicineToday’s Online CPD Journal superseded by more efficacious and/or Program. Log in to www.medicinetoday.com.au/cpd practical­ treatments. COMPETING INTERESTS: None. © ROSEDEPOSITMYPHOTOS/DEPOSITPHOTOS

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References

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