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A Review of Melasma, Part 1

A Review of Melasma, Part 1

Managing

A Review of Melasma, Part 1: Series Editor: Doris Hexsel, MD Etiopathogenic Factors, Clinical and Histopathologic Evaluations Jackson Machado-Pinto, MD, PhD, MSc; Maria de Fátima Melo Borges, MD; Geraldo Magela Magalhães, MD, PhD

elasma is a pigmentary disorder characterized Etiopathogenic Factors by the slow and progressive onset of hyper- Solar Radiation pigmented macules in sun-exposed areas, pre- The first manifestation of melasma has been associated M 1 dominantly on the face. It is seen mainly in healthy adult with excessive sun exposure, mainly during vacations women, but men may also be affected.2 in the summer months,1,4,5 but not necessarily with The word melasma, from the Greek melas (“black”), is sunburn. Until the 1960s, it was thought that primary used to describe acquired hyperpigmented conditions. melanization, which consists of an erythemal response Also used but less accurate is the term chloasma, from the (sunburn) followed by the formation of new pigment Greek cloazein, meaning “to be green.”3,4 (melanogenesis) and the migration of granules,7 Newcomer et al1 are responsible for one of the earliest could only be induced by the erythemogenic spectrum observations of an increased frequency of a characteristic (290–320 nm [UV] radiation). Pathak et al7 pigmentation, predominantlyCOS on the face. They calledDERM demonstrated that the formation of new melanin and attention to the influence of sun exposure on the onset immediate pigment darkening could be induced by long- and relapse of melasma, the absence of preceding inflam- duration (320–400 nm) UV radiation and visible light in mation, the more frequent distribution in characteristic the 400- to 650-nm spectrum, even when there was no areas of the face, the unpredictable evolution of the detectable damage to the cells. disease, and its refractoryDo nature despite Not therapy. They Copy documented an uneven increase in the overall melanin content of the basal cells of the , an absence of Pregnancy has been considered a frequent trigger of a dermal inflammatory infiltrate, and a normal aspect of melasma.4,5 A trial that involved 140 women with all the adnexal structures in their biopsies. Fitzpatrick phototype III and IV skin in the second half The true incidence of melasma is unknown.5 Halder et of pregnancy revealed skin changes that were considered al6 observed that pigmentary disorders, except for , physiologic. Pigmentary disorders with hyperpigmenta- were the third most common reason for dermatologic tion were the most frequently observed changes, with consultations in a group of 2000 black patients. The most melasma affecting 46% of the subjects. Of those patients, frequently observed pigmentary disorder was postinflam- 83% had their first manifestation of melasma during matory , followed by melasma. pregnancy, and 9.2% had their lesions persistently post- This column aims to review what has been learned partum. In 7.6% of patients, the lesions disappeared about melasma over the years, including the many meth- postpartum and relapsed in a later pregnancy.8 ods that have been used to evaluate this disease from both etiopathogenic and histopathologic standpoints. Cosmetics There are several reports of facial —Riehl´s melanosis or Hoffman-Habermann lichenoid toxic Dr. Machado-Pinto is Dermatologic Clinic Chief, and Drs. Borges melanodermatitis—that is partly related to the use and Magalhães are Cosmetic Department Coordinators, all from of cosmetics or to occupational exposure to irritating the Clínica Dermatológica, Santa Casa de Misericórdia, Belo or photosensitizing substances.1 Several components Horizonte, Minas Gerais, Brazil. of cosmetics, such as fatty acids, photoactive con- The authors report no actual or potential conflict of interest in taminants of mineral oils, petrolatum, beeswax, certain relation to this article. dyes, paraphenylenediamine, and perfume ingredients,

Vol. 19 No. 11 • november 2006 • Cosmetic 683 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

have been implicated as causative factors for dermal Lufti et al13 studied 108 nonpregnant women and melanoses. It is not known how the combination of sun found a significant association between thyroid autoim- exposure and the use of cosmetics can induce and/or munity and melasma, mainly in women who developed exacerbate melasma.4 melasma during pregnancy or after using hormonal con- traceptives. The frequency of was 4 times Associated Diseases higher in patients with melasma than in patients in the Endocrine abnormalities associated with melasma pre- control group. dominate, most likely because the skin is a competent endocrine organ able to produce, transform, and react to Drugs hormones. Because all the endocrine systems are linked Estrogen-progesterone therapies and oral contraceptives to one another, any change in amount and/or molecular are frequently related to melasma and other forms of skin structure of hormones could lead to an abnormal cuta- hyperpigmentation.4,5,14 This association has been attrib- neous response. In melanogenesis, hormones carry out uted to an increase in estrogen, progesterone, or MSH.4 functions of positive and negative regulation. Hormones MSH levels are increased in disease processes in which associated with positive regulation include andro- the skin is hyperpigmented, such as Cushing syndrome, gens, corticotropin, calcitriol, estrogen, progesterone, Addison disease, and chronic renal failure. In a study -stimulating hormone (MSH), and gluco- carried out by Thody et al,15 b-MSH levels were normal corticosteroids. Negative regulation is mediated by in patients in whom melasma was diagnosed late in . The melanocyte is a very sensitive target for pregnancy. Smith et al14 reported that b-MSH levels were steroids. There are specific receptors for each of the sex normal in patients who were using oral contraceptives, hormones in the skin. The density of such receptors and they suggested that the pigmentation in melasma varies according to body site, and there may be cross- may result from the direct effect of steroids on clones of reactivity with less affinity. Progesterone receptors are predisposed with normal b-MSH. distributed all over theCOS skin and are more numerous DERM A wide variety of chemicals, including arsenic, iron, than androgen and estrogen receptors.9 copper, bismuth, silver, gold, quinacrine, and phenyl- Perez et al10 studied 9 nonpregnant women (aged hydantoin, may cause skin hyperpigmentation, either 24–41 years) with melasma who had no known history through their deposition in the superficial layers of the of hormonal contraceptive use and were clinically normal skin or through their capacity to stimulate melanogen- from an endocrinologicDo standpoint. The Not patients with esis. 1,4Copy Sanchez et al4 studied 76 patients with melasma melasma had statistically significantly increased levels of and found no association between the disease and the use luteinizing hormone and lower levels of serum of any chemicals. than controls. This may represent subclinical evidence of mild ovarian dysfunction, which may underlie the patho- Other Factors genesis of some cases of idiopathic melasma. Race, genetics, nutrition, liver dysfunction, and parasitic Sacre et al11 evaluated the hormonal profiles of factors have been related in varying degrees to the devel- 20 women with idiopathic melasma. They studied their opment of melasma.4 Even though all racial groups are thyroid, gonad, and prolactin functions. The thyrotrophic, affected, melasma is more prevalent in individuals with prolactinic, and gonadotrophic reserves were normal, as Fitzpatrick phototypes IV to VI skin, especially women of were ovarian and thyroid functions. They concluded that Hispanic origin.5 More than 30% of melasma patients have it was not possible to make an etiopathogenic correlation a family history of the condition. Identical twins have been between melasma and hormonal profile. reported to develop melasma, while other siblings under Hassan et al12 studied the hormonal profiles of similar conditions did not.3 There is no evidence of asso- 36 women with melasma who were not using hor- ciation between occupational exposure and melasma.4 monal contraception and had regular menstrual cycles. The most important factor in the development of Twenty-seven patients had previously become pregnant melasma is exposure to sunlight. Genetic and hormonal and had not developed melasma. High levels of follicle- influences in combination with UV radiation are the 3,16 stimulating hormone, estradiol (E2-17b), and LH and 2 most important causes of melasma. low levels of prolactin were found in the follicular phase of the cycle of patients with melasma compared with Clinical Evaluation those in the control group. These findings suggest that As described by Newcomer et al,1 “the is estradiol may a role in the persistence of melasma. characterized by the insidious development of a blotchy

684 Cosmetic Dermatology • november 2006 • Vol. 19 No. 11 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

hyperpigmentation of the face in essentially healthy evaluate the outcome of treatment.17,22 The UV-detect adult women predominantly, although one man is camera is a 35-mm single-lens reflex camera equipped included in this series.” Melasma is a relatively common with Ultra 1200 electronic flash and Tri-X black- acquired symmetric hypermelanosis involving sun- and-white film, a 90-mm macro lens, and a 315- to exposed areas and is characterized by irregular light to 390-mm UV filter. The UV camera documents skin gray-brown macules with a distinct border, particularly pigment changes and demonstrates improvement after in the infraorbital region and the scalp margin.1,5 There therapeutic intervention.23 is no difference in the clinical presentation of melasma The colorimeter is a pulsed xenon arc lamp that con- between men and women.2 tains an optic fiber cable for measuring reflected illumi- Three clinical patterns of melasma were recognized on nation. Pigment changes were measured by the increase the basis of clinical examinations: centrofacial (cheeks, or decrease in light reflectance (designated as L*). The forehead, upper lip, nose, and chin), malar (cheeks and numerical range of L* is 0 (pure black) to 100 (pure nose), and mandibular (ramus of the mandibula). The white). The reflectance (L value) of white patients gener- centrofacial pattern is observed in the majority of cases, ally measures between 62 and 71.17,24,25 The colorimeter followed by the malar pattern and the mandibular pat- may be useful as a follow-up tool to evaluate the intensity tern.4 Kimbrough-Green et al17 studied a group of black of pigmentation during treatments.26 patients with melasma in whom malar distribution was Based on visible light and Wood light examination, more frequent. Although unusual, melasma can also melasma may be classified into 4 main types: epider- present on the forearms, perhaps due to hormone- mal, dermal, mixed, and unapparent. Using Wood light replacement therapy in postmenopausal women,18-20 and examination, the epidermal type shows an increase in on the neck.1,8 There is no association between clinical pigment not seen in dermal melasma, and the mixed presentation and etiologic factors. type of melasma shows an increase in pigment in Noninvasive complementary procedures to clinically certain areas and no increase in others. In a group of evaluate patients withCOS melasma have been developed DERM dark-skinned phototype V and VI patients with evident and include the Melasma Area and Severity Index melasma at visible light examination, the lesions can- (MASI), modified MASI (mMASI), conventional pho- not be seen at Wood light examination.4 Lawrence et tography, UV-detect camera, colorimetry, and Wood al24 compared the clinical efficacy of Jessner solution light examination. These procedures also help evaluate with that of glycolic acid and the ability of Wood light treatment outcome. Do Notexamination Copy to predict response to treatment. They con- The MASI is based on a scoring system devised for cluded that Wood light examination did not help predict . Four areas (A) of the face were evaluated for use treatment response. Ponzio et al27 concluded that, when in the calculation: forehead (F), right malar region (MR), classifying melasma, Wood light examination is not left malar region (ML), and chin (C), corresponding to sensitive enough, has low specificity, and results in an 30%, 30%, 30%, and 10% of the total face, respectively. average accuracy rate of 46%. For each region studied, A affected by melasma was given a score of 0 through 6 (05no melasma; 15,10%; Differential Diagnosis 2510%–29%; 3530%–49%; 4550%–69%; 5570%– Although clinical evaluation is usually sufficient to diag- 89%; 6590%–100%). Severity of melasma was based on nose melasma, there are a few situations in which other 2 factors, darkness (D) and homogeneity (H). D was rated clinical conditions may have to be ruled out: linear mor- on a scale of 0 (none) through 4 (severe), and H was rated phea (“en coup de sabre” [the stroke of a sword] type),28 on a scale of 0 (minimal) through 4 (maximal). The for- actinic ,29 melasmalike facial hyperpigmenta- 30 mula is: MASI50.3(DF1HF)AF10.3(DMR1HMR)AMR10.3 tion in acquired immune deficiency syndrome patients,

(DML1HML)AML10.1(DC1HC)AC. The maximum score for and acquired bilateral of Ota–like macules, a der- the MASI is 48, the minimum is 0.17 mal melanocytosis with positive dermal monoclonal anti- The mMASI calculates a defined portion of the demar- body NKI-beteb immunostaining.16 Hyperpigmentation cated right malar area. The calculation is based on the may occur with all of these conditions and, if localized numerical values assigned to A, D, and H. Therefore, to the face, histopathologic examination will have to be mMASI5(D1H) A.21 performed to confirm the diagnosis. One may also have Standardized conventional color photographs of the to consider Addison disease, drug-induced photosensitiv- same area, using the same equipment, lighting, pos- ity, mastocytosis, and of Civatte3,20 in the ing, photographer, and type of film, may be used to differential diagnosis of certain cases.

Vol. 19 No. 11 • november 2006 • Cosmetic Dermatology 685 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

Histopathologic Evaluation The 3-(3,4-dihydroxyphenyl) alanine (DOPA) reaction The histopathologic characteristics of melasma are not in melasma shows moderately to strongly DOPA-positive fully understood. Knowledge of its morphologic and melanocytes.4,16,33 The more intense positivity of the DOPA physiologic changes is essential to understanding the reaction in some structures of the melanocyte indicates pathogenesis of melasma. active and newly formed melanin granules, Two patterns of pigmentation are observed histo- which means that new melanin is being synthesized.7 pathologically: epidermal and dermal. In the epidermal Immunofluorescence studies demonstrate the absence type, the pigment is found predominantly in the basal of antihuman immunoglobulin (Ig) G, IgM, IgE, IgA, and suprabasal layers of the epidermis. A few melano- complement, and fibrinogen.4 phages may be found in the superficial . In the There is no difference between the histopathologic dermal type, the pigment is usually found inside histio- findings in melasma in women and men.2 Likewise, cytes in a perivascular situation in both the superficial there are no histopathologic differences in regard to and deep dermis.4 Histopathologic classification could clinical presentation.4,16 be useful both predictively and as a follow-up tool dur- Kang et al16 noted that, in both melasma and normal ing treatments.4,17,21,31,32 perilesional skin, there are signs suggestive of chronic When compared with normal skin in HE-stained sec- sun damage and that the proliferation of keratinocytes is tions, melasma skin shows a mild to moderate degree not the main event in the pathogenesis of melasma. They of rete ridge flattening and epidermal thinning and an suggest that the cause of melasma may be a stimulus increase in solar elastosis. Another morphologic find- that triggers melanocyte overactivity without necessar- ing is the presence of vacuolar degeneration of the basal ily leading to keratinocyte proliferation. However, they cells and focal vacuolar degeneration of the subbasement acknowledge that, although increased solar elastosis in membrane region.4 In Fontana-Masson–stained sections, melasma skin suggests that chronic sun damage may be the amount of melanin in melasma skin is increased in necessary for the development of the disease, it may also all epidermal layers. MCOSelasma skin has more free mela-DERMbe an epiphenomenon. nin and melanophages in the dermis. CD1a immuno- Based on the histopathologic findings above, one staining shows no changes in the number of epidermal may conclude that the main characteristic of melasma Langerhans cells in either lesional or normal skin. The is epidermal hyperpigmentation, probably due to mela- basal membrane is normal when sections stained with nocytes that present greater activity of melanogenic periodic acid-Schiff are Doexamined. Collagen Not is not altered enzymes, Copy associated with a dermis that displays evi- (Masson’s trichrome), nor are dermal nerve fibers (S-100). dence of photoaging. Verhoeff-van Gieson stains show thick, highly curled, and Some authors suggest that there is a specific type of more fragmented elastic fibers. Melanocyte immunostain- melanocyte that under a combination of multiple triggers, ing (NKI-beteb), one of the best available markers for such as persistent sun exposure, hormonal factors, and melanocytes, and tyrosinase-specific immunostaining genetic predisposition, undergoes functional changes, the (Mel-5) show that there are more melanocytes and more result of which is melasma.4,16 melanin in the epidermis of melasma skin.16 The following ultrastructural findings in melasma skin CONCLUSION have been reported: more abundant melanosomes in the The etiopathogenesis of melasma is not completely clear. stratum corneum; melanocytes with abundant perikaryon The melanocyte appears to be the most important ele- filled with well-developed mitochondria, Golgi apparatus, ment in the initiation of the disease process, and some endoplasmic reticulum, and ribosomes; melanocytes with believe that a specific type of melanocyte undergoes a stage III and IV melanosomes scattered singly through- functional change under the influence of certain factors, out the cytoplasm; vacuolar degeneration of melanocytes; such as solar radiation, hormones, and genetics, resulting greater number of melanosomes in basal and suprabasilar in disease. keratinocytes; intact and continuous basement membrane at Several methods for the clinical evaluation of melasma the dermoepidermal junction; and dermal melanophages.4,16 patients are currently available and should be more widely Ultrastructural observation of melasma skin shows an used so that the approach to diagnosing melasma, deter- increase in the number of both melanocytes and melano- mining disease prognosis, and treatment may become somes without any defect in the formation of the latter. The more objective and less empirical. maturational status, morphology, and distribution of mela- From the histopathologic point of view, melasma nosomes are similar to those found in normal skin.16 is characterized by an increase in the number and

686 Cosmetic Dermatology • november 2006 • Vol. 19 No. 11 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

activity of melanocytes, without keratinocyte prolifera- 17. Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al. Topical tion. There is no evidence that underlying sun damage is retinoic acid () for melasma in black patients. A vehicle- controlled clinical trial. Arch Dermatol. 1994;130:727-733. causally associated. 18. Johnston GA, Sviland L, McLelland J, et al. Melasma of the arms associated with hormone replacement therapy [letter]. Br J References Dermatol. 1998;139:932. 1. Newcomer VD, Lindberg MC, Sternberg TH. A melanosis of the 19. Varma S, Roberts DL. Melasma of the arms associated with hor- face (“chloasma”). Arch Dermatol. 1961;83:284-299. mone replacement therapy [letter]. Br J Dermatol. 1999;141:592. 2. Vazquez M, Maldonado H, Benmaman C, et al. Melasma in 20. o’Brien TJ, Dyall-Smith D, Hall AP. Melasma of the arms associ- men. A clinical and histologic study. Int J Dermatol. 1988;27: ated with hormone replacement therapy [letter]. Br J Dermatol. 25-27. 1999;141:592-593. 3. montemarano AD. Melasma. Available at: http://www.emedicine.com 21. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in /derm/topic260.htm. Accessed September 5, 2006. Asian patients with combined topical agents (retinoic acid, hydro- 4. Sanchez NP, Pathak MA, Sato S, et al. Melasma: a clinical, light quinone and hydrocortisone): clinical and histological studies. J microscopic, ultrastructural, and immunofluorescence study. J Am Dermatol. 1998;25:587-596. Acad Dermatol. 1981;4:698-710. 22. lee MH, Kim HJ, Ha DJ, et al. Therapeutic effect of topical application 5. Grimes PE. Melasma. Etiologic and therapeutic considerations. of linoleic acid and lincomycin in combination with betamethasone Arch Dermatol. 1995;131:1453-1457. valerate in melasma patients. J Korean Med Sci. 2002;17:518-523. 6. Halder RN, Grimes PE, McLaurin CI, et al. Incidence of common 23. 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Bandlike melasma mimicking 13. lufti RJ, Fridmanis M, MDoisrunas AL. Association Not of melasma with linearCopy (“en coup de sabre” type). Cutis. 1998;61:225-226. thyroid autoimmunity and other thyroidal abnormalities and their 29. Aloi F, Solaroli C, Giovannini E. Actinic lichen planus simulating relationship to the origin of melasma. J Clin Endocrinol Metab. melasma. Dermatology. 1997;195:69-70. 1985;61:28-31. 30. Gaddoni G, Baldassari L, Albertini F, et al. Melasma and acquired 14. Smith AG, Shuster S, Thody AJ, et al. Chloasma, oral contracep- immunodeficiency syndrome (AIDS). J Eur Acad Dermatol tives, and plasma immunoreactive beta-melanocyte-stimulating Venereol. 1995;4:44-47. hormone. J Invest Dermatol. 1977;68:169-170. 31. Kligman AM, Willis I. A new formula for depigmenting human 15. Thody AJ, Plummer NA, Burton JL, et al. Plasma b-melanocyte- skin. Arch Dermatol. 1975;111:40-48. stimulating hormone levels in pregnancy. J Obstet Gynaecol Br 32. Griffiths CE, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic Commonw. 1974;81:875-877. acid) improves melasma. A vehicle-controlled, clinical trial. Br J 16. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological Dermatol. 1993;129:415-421. characteristics in 56 Korean patients. Br J Dermatol. 2002;146: 33. mishima Y. Histopathology of functional pigmentary disorders. 228-237. Cutis. 1978;21:225-230. n

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