melasma actualizado

CONTINUING MEDICAL EDUCATION

Melasma: A comprehensive update

Part I

Vaneeta M. Sheth, MD,a and Amit G. Pandya, MDb

Boston, Massachusetts, and Dallas, Texas

Melasma is a common disorder of hyperpigmentation affecting millions of people worldwide. While it isthought to be triggered or exacerbated by sun exposure and hormones, much remains to be understoodabout its pathogenesis. A thorough understanding of the etiology of melasma and the research toolsavailable to study this condition are crucial to enhancing management and developing novel targetedtherapies of this often frustrating condition. ( J Am Acad Dermatol 2011;65:689-97.)

Key Words: chemical peels; chloasma; hydroquinone; laser therapy; melasma; pigmentation.

CME INSTRUCTIONS

The following is a journal-based CME activity presented by the American

Academy of Dermatology and is made up of four phases:

1. Reading of the CME Information (delineated below)

2. Reading of the Source Article

3. Achievement of a 70% or higher on the online Case-based Post Test

4. Completion of the Journal CME Evaluation

CME INFORMATION AND DISCLOSURES

Statement of Need:

The American Academy of Dermatology bases its CME activities on the

Academy’s core curriculum, identified professional practice gaps, the

educationalneedswhichunderlie thesegaps, andemergingclinical research

findings. Learners should reflect upon clinical and scientific information

presented in the article and determine the need for further study.

Target Audience:

Dermatologists and others involved in the delivery of dermatologic care.

Accreditation

The American Academy of Dermatology is accredited by the

Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

AMA PRA Credit Designation

The American Academy of Dermatology designates this journal-based

CME activity for a maximum of 1 AMA PRA Category 1 Credits�.

Physicians should claim only the credit commensurate with the extent of

their participation in the activity.

AAD Recognized Credit

This journal-based CME activity is recognized by the American Academy

of Dermatology for 1 AAD Recognized Category 1 CME Credits and may

be used toward the American Academy of Dermatology’s Continuing

Medical Education Award.

Disclaimer:The American Academy of Dermatology is not responsible for statements made by the author(s).

Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect

the official policy of the American Academy of Dermatology. The information provided in this CME

activity is for continuing education purposes only and is not meant to substitute for the independent

medical judgment of a healthcare provider relative to the diagnostic, management and treatment

options of a specific patient’s medical condition.

Disclosures

Editors

The editors involved with this CME activity and all content validation/

peer reviewers of this journal-based CME activity have reported no

relevant financial relationships with commercial interest(s).

Authors

Dr. Pandya has been an investigator and consultant for Galderma

Laboratories within the last 5 years and has received grants and

honoraria for these services. Dr. Sheth reported no relevant financial

relationships with commercial interest(s).

Planners

Matthew Zirwas, MD, served as a peer reviewer for this CME activity and

is a speaker and consultant for Coria Laboratories and has received

honoraria for these services. He is also a consultant for Onset

Therapeutics and has received honorarium for this service. The other

planners involved with this journal-based CME activity have reported no

relevant financial relationships. The editorial and education staff in-

volved with this journal-based CME activity have reported no relevant

financial relationships with commercial interest(s).

Resolution of Conflicts of Interest

In accordance with the ACCME Standards for Commercial Support of

CME, the American Academy of Dermatology has implemented mech-

anisms, prior to the planning and implementation of this Journal-based

CME activity, to identify and mitigate conflicts of interest for all

individuals in a position to control the content of this Journal-based CME

activity.

Learning Objectives

After completing this learning activity, participants should be able to

describe the epidemiology of melasma; delineate the pathogenesis of

melasma; and describe the appropriate diagnostic workup of a patient

with suspected melasma.

Date of release: October 2011

Expiration date: October 2012

� 2010 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2010.12.046

689

Melasma is a common disorder of hyperpigmen-tation that affects more than 5 million people in theUnited States alone.1 Found most commonly inwomen with Fitzpatrick skin phototypes III throughV living in areas of intense ultraviolet (UV) lightexposure, melasma is often difficult to treat and has asignificant negative impact on patients’ quality oflife.2-6 The avoidance of ex-acerbating factors such as UVlight and hormonal contra-ceptives and testing for un-derlying thyroid disorderscan lead to improvement incertain subsets of patients.Recent studies, however,have shown that the under-lying basis for melasma maybe more complex than orig-inally thought. These find-ings also provide newavenues for research intobetter understanding andtreating this challengingcondition.

Melasma is an acquireddisorder of symmetrical hy-perpigmentation appearingas light brown to dark, muddy brown maculesand patches on the face, especially the forehead,malar areas, and chin. It is also sometimes referredto as chloasma or the mask of pregnancy, a termused in the dermatology literature for several de-cades.7 The term chloasma comes from the Greekchloazein, meaning to be green,8 whereas the termmelasma comes from the Greek melas, meaningblack.

EPIDEMIOLOGYKey pointsd The reported prevalence of melasma rangesfrom 8.8% among Latino females in theSouthern United States to as high as 40% inSoutheast Asian populations

d Melasma predominantly affects Fitzpatrickskin phototypes III and IV and often lasts formany years after pregnancy

Several studies from around the world haveattempted to discern the prevalence of melasma inthe general population; however, few have ran-domly sampled the general population (Table I). In

a randomized study involv-ing self-reporting of melasmain a Hispanic female popula-tion in Texas, Werlinger et al9

noted the prevalence to be8.8%, with an additional 4%reporting melasma in thepast. In Southeast Asia, theprevalence has been re-ported to be as high as 40%in females and 20% inmales10; however, thesewere patients presenting toa dermatology clinic, indicat-ing some ascertainment bias.A survey of Arab Americansliving in the United Statesfound that melasma was thefifth most commonly re-

ported skin condition, mentioned by 14.5% of peo-ple surveyed.11 A recent multicenter survey offemales from nine countries found that Fitzpatrickskin phototypes III and IV were most commonlyaffected, and that African Americans were morelikely to have a positive family history of melasma.12

It was also noted that 41% of women surveyed hadonset of disease after pregnancy but before meno-pause. Importantly, only 8% noted spontaneousremission. Only 25% of patients taking oral contra-ceptives had an onset of melasma after starting theircontraceptive. While melasma was thought to be apregnancy- and contraceptive-related disorder in thepast, recent studies show that in many patients it is achronic disorder that may last for decades. Althoughcommon, there is much to learn about the epidemi-ology of melasma worldwide.

CLINICAL AND PATHOLOGIC FEATURESKey pointsd The centrofacial pattern of melasma is themost common

d While a Wood lamp examination was previ-ously thought to accurately predict epider-mal versus dermal pigment deposition,recent studies have shown that dermal mel-anin deposition is common and may beunderrecognized

CAPSULE SUMMARY

d Melasma is a common disorder ofhyperpigmentation found in all parts ofthe world that significantly affectsquality of life; it is exacerbated by sunexposure and hormonal factors, makingphotoprotection and avoidance oftrigger factors a critical part ofmanagement.

d Recently identified pathogenic factorsinclude stem cell factor and c-kit alongwith neural and vascular growth factors.

d An increased understanding of theetiology of melasma will aid in thedevelopment of novel therapies.

From the Departments of Dermatology at Brigham and Women’s

Hospital,a Harvard Medical School, and the University of Texas

Southwestern Medical Center,b Dallas.

Funding sources: None.

Reprints not available from the authors.

Correspondence to: Amit G. Pandya, MD, Department of

Dermatology, The University of Texas Southwestern Medical

Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9190. E-mail:

[email protected].

0190-9622/$36.00

J AM ACAD DERMATOL

OCTOBER 2011690 Sheth and Pandya

elia

Resaltado

d Melasma may be caused by the presence ofmore biologically active melanocytes in theaffected skin, rather than an increase inmelanocytes

Several clinical patterns of melasma have beendescribed, but many patients have a mixture of thesepatterns (Figs 1-5).13 The centrofacial pattern is themost common and consists of lesions on the fore-head, cheeks, nose, upper lip, or chin. The malarpattern describes lesions located primarily on thecheeks and nose. The mandibular pattern consists oflesions on the ramus of the mandible. This latterpattern may actually be a form of poikiloderma ofCivatte, because patients are often postmenopausaland biopsy specimens reveal significant actinic dam-age.14 Although melasma of the forearms has beendescribed, this entity is not always present in patientswith facial melasma and has not been well charac-terized.15 Melasma can be further classified based ona Wood lamp examination to help identify thelocation of the pigment.16 Lesions that are enhancedwhen viewed under a Wood lamp imply increasedepidermal melanin content, whereas those that arenot enhanced with a Wood lamp examination implyan increase in dermal melanin content. Lesions thathave both enhancing and nonenhancing areas aresaid to have a mixed pattern. Recent histologicstudies indicate that this construct may not beaccurate.

Few histopathologic studies have been performedon melasma, but several recent publications haveprovided new insight into its pathogenesis. A study bySanchez et al13 examined biopsy specimens of le-sional skin. The authors found two basic patterns ofmelasma: an epidermal form that featured melanindeposition mainly in the basal and suprabasal layers

andmelanocytes thatwere highly dendritic and full ofpigment, and a dermal formwith superficial and deepperivascular melanophages in the dermis with no-ticeably less prominent epidermal pigmentation.Electronmicroscopy revealed highly melanized stage

Table I. Worldwide prevalence of melasma

Author Location Sample population

No. of patients

sampled

Percent of cases

with melasma

Werlinger et al9 Dallas/Fort Worth, TX Random sample ofLatino women in thegeneral population

500 8.8%

Sanchez37 New York, NY Latinos private clinic 1000 8.2%Latinos Hospital clinic 1000 4.1%

Failmezger38 Cuzco, Peru Incas dermatology clinic 1277 10.1%Parthasaradhi

and Al Gufai39Hail, Saudi Arabia Dermatology clinic 3298 2.88%

Sivayathorn10 Bangkok, Thailand University dermatologyclinic

679 33%

Hiletework40 Addis Ababa, Ethiopia Dermatology clinic 7760 1.8%Tomb and Nassar41 Beirut, Lebanon Dermatology clinic 6822 patients examined

over a 5-year period3.4%

Fig 1. Melasma involving the cheek, showing inhomoge-neous pigmentation.

J AM ACAD DERMATOL

VOLUME 65, NUMBER 4Sheth and Pandya 691

IV melanocytes in lesional skin. Importantly, a Woodlamp examination of lesional skin correlated with theresults of thebiopsy; that is, patientswhowere judgedto have epidermal melasma clinically also had prom-inent epidermal hyperpigmentation on light micro-scopic examination. Expanding on this work, Grimeset al17 studied patients with Fitzpatrick skin photo-types IV through VI with epidermal and mixedmelasma by Wood lamp examination and examinedbiopsy specimens both from lesional skin and nearbynormal-appearing skin.17 Unlike previous studies,they found that despite a Wood lamp evaluationindicating epidermal melasma in some patients, allsamples examined had increased melanin depositionin the epidermis and dermis. They further used Mel-5staining to show that there was no increase in mela-nocyte number, but themelanocytes themselveswerelarger and had more prominent dendritic processes.This last finding was confirmed with electron micros-copy. Therefore, patients with apparent epidermalmelasma after a Wood lamp examination may havesignificant melanin in the dermis.

A similar study by Kang et al18 evaluated thehistopathologic characteristics of melasma skin

compared to nearby normal-appearing skin inAsian patients, showing that melasma skin hadmore severe solar elastosis, a greater number ofepidermal melanocytes, more dermal free melaninand melanophages, and significantly increased mel-anin in all layers of the epidermis. Interestingly, therewas no difference in the number of Langerhans cells,appearance of the basement membrane, or collagenbetween the involved and uninvolved areas; how-ever, there was increased elastic fiber fragmentationin the melasma skin. Furthermore, melanocytes inmelasma skin had more dendrites, mitochondria,Golgi, and rough endoplasmic reticulum, suggestingthat they were more biologically active than theircounterparts in normal skin. The presence of dermalmelanin and melanophages in these studies mayexplain the difficulty in treating patients with appar-ent epidermal melasma.

ETIOPATHOGENESISKey pointsd The high incidence of melasma among fam-ily members suggests a genetic component

Fig 2. Melasma of the cheek. Fig 3. Melasma of the lateral cheek.

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d Sun exposure is a commonly reported exac-erbating factor, likely because of theUV-induced upregulation of melanocyte-stimulating cytokines

d While melasma is known to occur with hor-monal changes, clinical evidence to datedoes not clearly associate serum hormonelevels to melasma

d For women who note the onset of melasmaafter beginning a course of an oral contra-ceptive, the medication should be stopped ifpossible

While the exact underlying etiology for melasmaremains a mystery, several well known risk factorsexist. Melasma is more common in darker skin types,particularly Fitzpatrick skin types III and IV. Otherreported risk factors include genetic predisposition,exposure to ultraviolet light, pregnancy, and exog-enous hormones (ie, oral contraceptives andhormone replacement therapy).1 A genetic predis-position is suggested by a high reported incidence infamily members in several studies. An Iranian surveyof pregnant women with melasma reported a 54.7%

incidence of melasma in a family member.19 A similarstudy from Singapore20 revealed a positive familyhistory of melasma in 10.2% of study subjects, and inLatino men, Vasquez et al21 found a positive familyhistory in 70.4% of study subjects. Forty-eight per-cent of 324 women in a global survey reported afamily history of melasma.12

UV light is a commonly reported initiating orexacerbating factor for melasma, likely because of itseffects on melanocytes and on cytokine production.Melasma occurs in sun-exposed areas, and manypatients report an increased severity of melasmawithsun exposure. One reason for this appears to be thatUV radiation induces melanocyte proliferation,migration, and melanogenesis. In addition, UVradiation can lead to the production of multiplecytokines, including interleukin-1, endothelin-1,alphaemelanocyte-stimulating hormone (a-MSH),and adrenocorticotropic hormone (ACTH) from ke-ratinocytes, which in turn upregulate melanocyteproliferation and melanogenesis. Examining the lo-cal expression of cytokines in lesional and perile-sional skin from 10 Korean women, Im et al22 used

Fig 4. Melasma of the cheek, temple, forehead, and upperlip.

Fig 5. Melasma predominantly involving the foreheadand mandible.

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immunohistochemistry to show that a-MSH wasexpressed to a greater degree in lesional melasmaskin in the stratum spinosum and stratum granulo-sum than in perilesional skin. There was, however,no difference in the amount of melanocortin-1 re-ceptor or ACTH expression. These findings suggestthat sustained overexpression of MSH in lesional skinafter UV exposure may be a significant factor for thedevelopment of melasma.

The hormonal link to melasma is not clearlyelucidated. Many patients note the onset or worsen-ing of disease with pregnancy or oral contraceptiveuse, and several studies have sought to clarify theroles of particular hormones in the pathogenesis ofmelasma. Melanocytes from healthy skin have beenshown to express both nuclear and cytosol estrogenreceptors.23 Lieberman et al24 revealed by immuno-histochemical staining that lesional melasma skinhad increased estrogen receptor expression as com-pared to nearby normal skin. In addition, incubationof melanocytes from normal skin with estradiol hasbeen found to increase the proliferation of melano-cytes but downregulate tyrosinase activity and mel-anogenesis.23 A similar study found that melanocytesfrom healthy skin increase in size and produce moretyrosinase when incubated with MSH, ACTH, lutei-nizing hormone (LH), and follicle-stimulating hor-mone (FSH).25 Interestingly, estradiol, estriol, andprogesterone incubation led to increased cell prolif-eration, but to a lesser degree, and did not increasetyrosinase activity. It is still unclear why certain areasof the face are predisposed to developing melasmawhile others are not involved. Hormone receptorsand blood vessels may play a role, but other factors,such as sebaceous gland density and activity, pho-totoxicity, and antioxidants, may also be involved.

Perez et al26 examined the link between circulat-ing levels of hormones and their relationship tomelasma. The authors found that nulligravid womenwith melasma had significantly higher serum levelsof LH and lower levels of estradiol than their coun-terpart controls. The authors also found that therewas no difference in serum levels of beta MSH(b-MSH), ACTH, FSH, progesterone, prolactin, thy-roid hormone, or cortisol between the two groups. Insummary, there is some evidence of a hormonalcomponent in the pathogenesis of melasma, but theavailable data are conflicting, possibly because of thevaried genetic backgrounds of the different studypopulations. Further research into the effects ofhormones on melasma is needed.

While the exact link between hormones andmelasma remains unclear, several studies have notedthe onset of melasma with oral contraceptive use. In1967, Resnick27 studied the records of 212 female

patients in an obstetrics and gynecology clinic andnoted that 29% of patient being followed developedmelasma as a direct result of oral contraceptive use.27

Of these patients, 87% also developed melasmaduring pregnancy. In this cohort of women, decreas-ing the estrogen component of the oral contraceptivepill did not affect incidence of melasma. In morerecent work by Ortonne et al,12 of 324 women beingtreated for melasma in dermatology clinics in severalcountries, 25% reported the initial onset of melasmawith oral contraceptive use. The rates were higher inpatients without a positive family history ofmelasma.Therefore, while the exact link between hormonesand melasma has yet to be clearly defined, it isrecommended that patients who develop melasmawhile taking an oral contraceptive pill should stopthe medication and avoid the future use of suchdrugs when possible.

Other less commonly reported risk factors includethyroid disorders, phototoxic medications, and cos-metics. While evaluating thyroid hormone levels infemale Argentinean patients with melasma, Lutfiet al28 found that women who developed melasmaduring pregnancy or while taking oral contraceptiveshad a 70% incidence of mild thyroid abnormalitiescompared to 39% of those with idiopathic melasma.In addition, patients with melasma from any etiologywere four times more likely to have thyroid abnor-malities than age- and sex-matched controls. Thesefindings suggest that thyroid disorders are related tomelasma, particularly in those with pregnancy- ororal contraceptiveeassociated melasma, but thisneeds to be confirmed in larger studies.

Several new papers have shed some light on therole of stem cell factor in the pathogenesis ofmelasma. Examining samples of lesional and nonle-sional skin, Kang et al29 found that lesional melasmaskin had a greater expression of stem cell factoraround dermal fibroblasts and a greater expressionof c-kit in the basal layer of the epidermis. Grichniket al30 revealed that stem cell factor can increasemelanocyte number, size, and dendricity when in-jected into human skin explants. A trial evaluatingbreast cancer patients receiving subcutaneous injec-tions of recombinant human stem cell factor foundthat five out of 10 patients developed persistenthyperpigmentation at the injection site.31 Light mi-croscopy confirmed an increase in epidermal mela-nization and numbers of melanocytes.

Recent studies have also examined the possibilityof a neural component to melasma. Bak et al32

obtained biopsy specimens of both lesional andadjacent nonlesional skin in six Asian females withmelasma. Staining for nerve growth factor receptor(NGFR) revealed increased numbers of

J AM ACAD DERMATOL


keratinocytes expressing NGFR and more hypertro-phic nerve fibers in the superficial dermis of lesionalcompared to nonlesional skin. While intriguing, thesmall sample size limits the generalizability of theseresults.

Finally, melasma may also have a vascular com-ponent in its pathogenesis. Kim et al33 found thatbiopsy specimens of lesional melasma skin hadgreater vascular endothelial growth factor expres-sion in keratinocytes compared to nearby nonle-sional skin. Factor VIIIerelated antigen stainingshowed that melasma skin had more numerousand larger blood vessels compared to uninvolvedskin. Furthermore, using tristimulus colorimetry spe-cifically measuring redegreen wavelengths, the au-thors found that involved skin had higher values forthis variable, implying that the clinical observation ofincreased vascularity correlates with histopathologicfindings.

In summary, there appears to be a complexinterplay of hormonal and environmental factorsthat predispose certain patients to developing me-lasma. The presence of local hormones in the skinmay play a greater role than originally thought.While the exact link between hormones and me-lasma is not clear, it is recommended that patientswho develop melasma while taking an oral contra-ceptive should stop the medication when possible.Additional work in this area is needed to helpelucidate the underlying pathogenesis of thiscondition.

Differential diagnosisDisorders that can be confused for melasma

include postinflammatory hyperpigmentation, solarlentigines, ephelides, drug-induced pigmentation(Fig 6), actinic lichen planus, facial acanthosisnigricans (Fig 7), frictional melanosis, acquired bi-lateral nevus of Otaelike macules (Hori’s nevus),and nevus of Ota.34,35 These can sometimes coexistin patients with melasma, making distinction impor-tant when devising treatment plans or enrollingpatients for clinical trials. A careful medial history,an examination of the skin including a Wood lampexamination, the recognition of concomitant inflam-matory disorders, and a skin biopsy specimen are allhelpful in making the correct diagnosis.

Studying melasma: The Melasma Area andSeverity Index

Good outcome measures are important in evalu-ating the effectiveness of therapies. The MelasmaArea and Severity Index (MASI) was created byKimbrough-Green et al36 in an attempt to standard-ize the subjective evaluation of melasma. It is

calculated by dividing the face into four areas: theforehead, right malar area, left malar area, andchin.36 Each area is weighted such that the forehead,right malar area, and left malar area are 30% each,and the chin is 10%. Scoring for darkness of pigmentwhen compared with normal skin and homogeneityof the pigment in the specified area is then per-formed. A numerical value for area of involvement,ranging from 1 (\10% of the area involved) to 6 (90-100% of the area involved) is assigned. The totalscore is calculated as follows:

MASI ¼ 0:3A ðD1HÞ½forehead�

10:3A ðD1HÞ½R malar�

10:3A ðD1HÞ½L malar�

10:1A ðD1HÞ½chin�

The range of scores is 0 to 48. The MASI score isthe most commonly used measurement technique

Fig 6. Minocycline hyperpigmentation, a mimicker ofmelasma.

Fig 7. Acanthosis nigricans mimicking melasma.

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for the study of melasma; however, validation andreliability testing of this index has not yet beenreported.

QUALITY OF LIFE STUDIES: MEASURINGTHE IMPACT OF MELASMAKey pointsd Validated questionnaires in several popula-tions have shown that even a small amountof melasma can cause significant emotionaland psychological distress

d Patients with lower levels of education orunderlying psychiatric disorders may be atgreater risk of emotional impairment

Melasma is often psychologically distressing inaffected patients. The most commonly used tool forassessment of quality of life in patients with melasmais the MelasQoL.2 This questionnaire was developedby modifying items from the SKINDEX-16 and skindiscoloration questionnaire. By surveying 102women with melasma, the authors found that theareas most impacted by the disease were social life,recreation/leisure, and emotional well being. Theseresults correlated well with results from theSKINDEX-16 and the Dermatology Life QualityIndex (DLQI) questionnaires, validating theMelasQoL. Interestingly, the effect of melasma onquality of life was not correlated with the severity ofmelasma, suggesting that even a small amount ofpigmentation can take a significant emotional toll.The benefit of the MelasQoL is that it does not weighphysical and psychological distress equally, which isimportant for disorders of pigmentation, which lackscaling, pruritus, pain, and other types of physicalimpairment. This questionnaire has since been trans-lated into Spanish and Portuguese and thus far hasbeen shown to be readily adaptable to other cul-tures.3-6 In the Spanish version, patients with little tono education were found to have higher scores,indicating greater emotional and psychological bur-dens of disease in this subset of patients, while thePortuguese study found higher scores in patientswith underlying psychiatric disorders. It is clear thatmelasma significantly affects quality of life, and itseffect on a particular patient may be profound.

Melasma involves a complex interaction of envi-ronmental, hormonal, and cellular factors, and newresearch has increased our understanding of thisdisease—but much work still needs to be done.Additional studies to understand the genetic path-ways that trigger melasma and to identify the roles ofcellular growth factors in the pathogenesis of me-lasma are needed, because these may serve as newtargets for therapy. In addition, the role of hormones

in initiating or exacerbating melasma still needs to bebetter clarified. Given the impact that this conditionhas on patients’ quality of life and the lack of highlyeffective treatment options, additional research intounderstanding the biologic basis of this disease willbe crucial to developing more effective treatmentoptions.

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Answers to CME examination

Identification No. JA1011

October 2011 issue of the Journal of the American Academy of Dermatology.

Questions 1 and 2, Sheth VM, Pandya AG. J Am Acad Dermatol 2011;65:689-97.

1. c2. d

J AM ACAD DERMATOL


elia

Nota adhesiva

?

melasma actualizado

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