Ebook Treatment for skin color: Part 2

(BQ) Part 2 book Treatment for skin color presents the following contents: Pigmentary disorders, follicular disorders and alopecias, tumors benign and malignant, cosmetics, complementary and alternative medicine.

Pigmentary Disorders PART 2

Part 2 Pigmentary Disorders

10

Hyperpigmented

Disorders

David A Rodriguez

Acanthosis nigricans 183

Benign melanonychia 185

Confluent and reticulated papillomatosis of Gougerot and Carteaud (CRPGC) 187

Drug-induced pigmentation 189

Erythema dyschromicum perstans 191

Exogenous ochronosis 192

Gingival hyperpigmentation 194

Melasma 195

Mongolian spots 199

Nevus of Ota 201

Pigmentary demarcation lines 203

Post-inflammatory hyperpigmentation (PIH) 204

Solar lentigines 207

Pediatric perspectives: Transient neonatal pustular melanosis 209

Acanthosis nigricans

Classical acanthosis nigricans (AN) is characterized by

sym-metrical areas of verrucous, brown to black, velvety plaques,

typically located on the posterior and lateral neck and axillae.1,2

Flexor surfaces, of the extremities, inframammary folds and

perianal area may also be affected.3 Interestingly, patients often

refer to the appearance of the lesions as a ‘dirty area’, which

they are known to vigorously scrub (Fig 10.1)

The etiology of AN is unknown However, if the onset of lesions is rapid and the lesions are generalized, then malig-nancy must be suspected and an evaluation undertaken.4

AN can be seen in a wide range of individuals, from those completely healthy as a normal variant to those with underly-ing medical conditions, although it is most often observed in darker pigmented individuals One source reports the inci-dence of AN as 13%, 6% and 1% in African-Americans, Latinos and Caucasians respectively.5

AN is also believed to be a marker of endocrine distur-bances, namely increased insulin secretion and insulin resist-ance.6 Therefore the most common type of AN is associated with conditions with an elevated insulin blood level, such as

in diabetes and obesity There are many other possible causes

of AN, including:

• Hypothyroidism

• Addison’s Disease

• Pituitary disorders

Medications associated with AN,

• Insulin6

• Glucocorticoids

• Growth Hormone

• Diethylstilbestrol

• Vitamin B3 (Niacin)

• Methyltestosterone

• Oral contraceptives.7 The mainstay of AN treatment is management of the under-lying disease If AN occurs as a result of obesity, weight loss is required.4,6 If malignancy is the underlying cause, successful surgery or chemotherapy will ameliorate AN

Topical treatments such as salicylic acid or tretinoin may be helpful in some individuals Lasers or dermabrasion have also been used successfully, especially with veruccous protrusions

If AN is attributed to an offending agent, discontinuation of the drug should lead to resolution

topical 0.1% tretinoin gel (retinoic acid) 2 times daily for a 2-week trial period The right axilla served as the control After the initial trial period, there was nearly complete resolution of clinical lesions in the left axilla.

Topical therapy with tretinoin and ammonium lactate for acanthosis nigricans associated with obesity Blobstein SH

Cutis 2003; 71(1):33–34

This study reports the successful use of a combination of 12% ammonium lactate cream and 0.05% tretinoin cream to treat AN associated with obesity

Topical tretinoin in acanthosis nigricans Lahiri K,

Malakar S Indian J Dermatol Venerol Leprol 1996; 62: 159–161

Efficacy of topical tretinoin was assessed in 30 cases of idiopathic acanthosis nigricans which were recalcitrant to conventional modalities of treatment Topical tretinoin 0.05% qhs was found to be very effective both clinically and histologically

Treatment of acanthosis nigricans with oral isotretinoin

Katz RA Arch Dermatol 1980; 116(1):110–111

This article describes a patient with extensive acanthosis nigricans who was treated successfully with oral isotretinoin

to test its effectiveness in disorders of keratinization Selection

of this disease for treatment with a oral retinoid agent was based on the success of using topical tretinoin in patients with acanthosis nigricans

Comparison of metformin versus rosiglitazone in patients with acanthosis nigricans: a pilot study Bellot-Rojas P,

Posadas-Sanchez R, Caracas-Portilla N, et al J Drugs Dermatol 2006; 5(9):884–889

The aim of this 12-week randomized, open-label pilot study was to compare the efficacy of metformin versus rosigli-tazone on AN lesions of the neck as well as their effects on metabolic and anthropometric variables Overweight or obese subjects with AN were randomized to either metformin (n = 4) or rosiglitazone (n = 3) Only the rosiglitazone group showed a significant reduction in insulin levels No effect on the severity of AN was observed, but modest improvements

of skin texture occurred in both treatment groups Results showed that metformin and rosiglitazone were well tolerated Although efficacy on skin lesions was very modest, their use in acanthotic subjects might be useful during longer treat-ment periods

Hyperkeratosis of the nipple associated with acanthosis ricans: treatment with topical calcipotriol Lee HW, Chang

nig-SE, Lee MW, Choi JH, Moon KC, Koh JK J Am Acad Dermatol 2005; 52(3 Pt 1):529–530

A 26-year-old obese woman presented with a 7-year history

of asymptomatic, hyperpigmented, hyperkeratotic lesions on both nipples; velvety, hyperpigmented patches on both axillae and groin; and hyperpigmented papillary papules on the tip

of the tongue, that began after a 10 kg weight gain over a 3-month period She was diagnosed with hyperkeratosis of the

First-Line Therapies

Figure 10 1: (A) Acanthosis nigricans on the lateral neck (B) Acanthosis

nigricans in the axilla

A

B

Treatment of acanthosis nigricans with tretinoin Darmstadt

GL, Yokel BK, Horn TD Arch Dermatol 1991; 127(8):

1139–1140

This case report details the treatment of a 55-year-old

Indian man with AN involving the axillae, popliteal fossae, the

dorsal surface of his toes and the posterior aspect of his neck,

as well as a general darkening of his complexion, that began

after taking nicotinic acid 500 mg TID for

hypercholestero-lemia After 16 weeks of treatment, the patient’s cholesterol

value dropped significantly; however, the skin changes were

cosmetically unacceptable The left axilla was treated with

10 Hyperpigmented Disorders • Benign melanonychia

resolve with weight loss Therefore, these patients should be counseled regarding weight reduction and diet modification.When a concomitant pathologic process has been ruled out, one can safely assume AN is benign Benign hereditary forms

of acanthosis also exist In the aforementioned cohort, metic treatment should be offered

3 Pollitzer S Acanthosis nigricans: a symptom of a disorder of the abdominal sympathetic J Am Med Assoc 1909; 53:1369–1373.

4 Kahn CR, Flier JS, Bar RS, et al The syndromes of insulin resistance and acanthosis nigricans: insulin-receptor disorders in man N Eng J Med 1976; 294:739–745

5 Kim NY, Pandya AG Pigmentary Diseases Med Clin North Am 1998; 82(5):1185–1207

6 Curth HO Acanthosis nigricans Birth Defects 1971; 7:31–39

7 Stals H, Vercammen C, Peeters C, Morren M-A Acanthosis nigricans caused by nicotinic acid: case report and review of the literature Dermatology 1994; 189:203–206.

nipple associated with AN and treated with topical calcipotriol

ointment twice daily After 3 months, the lesions on both

nipples were significantly improved

Commonly encountered pitfalls

Although acanthosis nigricans commonly occurs on the neck,

it is important not to overlook other locations such as the

axillae, lateral cheek and chest

The finding of acanthosis nigricans, especially in an

over-weight patient, is likely a marker of insulin resistance, diabetes

mellitus or another endocrine abnormality As such, referral

to an endocrinologist should be initiated

However, while clinicians reflexively focus on

endocrinopa-thies, acanthosis may also indicate an underlying malignancy,

especially in adults Gastric carcinoma is one such associated

malignancy Hence, a thorough evaluation for malignancy is

indicated

Special management & counseling considerations

If evidence of insulin resistance or diabetes mellitus is not

found in overweight patients, it is likely that the condition will

Benign melanonychia

Melanonychia is a longitudinal or transverse brown streak

involving the nail plate or alternatively, complete

discolora-tion of the plate Longitudinal melanonychia also termed,

melanonychia striata, is the most common presentation.1 It

can present as a single band on one or more digit although

the entire nail plate may also be involved Figure 10.2 illustrates

such a case Transverse melanonychia is an uncommon

condi-tion caused by radiacondi-tion therapy and chemotherapy A quite

interesting study outlines 3 cases caused by the use electron

beam therapy.2

More prevalent in individuals of color, benign

melanony-chia may be associated with the normal aging process.1,3 Up

to 100% of African Americans older than 50 years of age

exhibit melanonychia, termed racial melanonychia.4 A study

of 800 Japanese individuals found the prevalence of

mela-nonychia at 20% and 23% for males and females respectively.5

It is a much rarer phenomenon among Caucasians.6

There are many causes of melanonychia both benign

and malignant.7,8 The physiologic processes responsible for

melanonychia are melanocyte activation and melanocyte

hyperplasia The majority of cases of melanonychia occur as a

result of melanocyte activation, during which hypermelanotic

melanocytes are taken up from the nail bed and incorporated

into the nail matrix.7 Dominguez and Martin biopsied 68 patients with longitudinal melanonychia and determined that 68% had racial melanonychia, 5.7% benign melanocytic hyperplasia and 5.7% a nail malignancy.9

The following common etiologies of melanonychia involve melanocyte activation:4

• Drug-induced:

– Antimalarials– Antiretrovirals– Chemotherapeutic agents (doxorubicin, cyclophospha-mide, and hydroxyurea)

– Metals

• Post-inflammatory:

– Chronic paronychia– Onychotillomania (nail biting)– Friction/trauma

• Infectious:

– Onychomycosis

• Systemic causes– Endocrinopathies

• Benign tumors:

– Myxoid cysts– Verrucae

• Non-melanocytic malignant causes:

– Bowen’s disease– Squamous cell carcinoma

Commonly encountered pitfallsWhile longitudinal melanonychia is a common and often normal finding in individuals with dark skin, the clinician should not lower his or her index of suspicion for subungual melanoma Additionally, melanoma should be suspected in patients with lighter skin tones who have melanonychia It is imperative that a biopsy specimen be obtained from the nail matrix to ensue the diagnosis of melanoma, as a nail plate biopsy will not be sufficient.

Special management & counseling considerationsSkin of color patients are often unaware that melanoma may present as longitudinal melanonychia Therefore, education regarding this possibility and self-examination is important They should also be counseled to have yearly cutaneous examinations by a dermatologist including fingernails and toe-nails Finally, patients undergoing nail matrix biopsy, should

be warned regarding possible permanent post-biopsy nail distrophy

4 Tosti A, Piraccini BM, de Farias DC Dealing with melanonychia Semin Cutan Med Surg 2009; 28(1):49–54.

5 Tasaki K On band or linear pigmentation of the nail Jpn J Dermatol 1933; 33:568.

The following conditions are caused by melanocytic

hyper-plasia and can also lead to ML:4

• Lentigo/benign melanocytic hyperplasia

• Nail matrix nevi

• Melanoma

Melanonychia induced by chemotherapy is reversible and

most commonly occurs when the patient is treated with drugs

like doxorubicin, cyclophosphamide, and hydroxyurea

Evaluation of melanonychia includes a thorough

inspec-tion of the nail and associated structures, such as the proximal

and lateral nail folds and hyponychium, as well as the exact

location of the pigmentation.9 In order to assist the clinician

distinguish benign from malignant longitudinal

melanony-chia, Levit et al proposed the following guidelines for

malig-nant melanonychia.4

• A – Age (peak incidence in the fifth to seventh decade)

• B – Brownish-black band with breadth greater than 3 mm

• C – Change in morphology

• D – Digit that is involved (The thumb is more likely than

the great toe; the great toe more likely than the index

finger.)

• E – Extension of the brownish-black pigment of the

nail bed, nail matrix, and nail plate onto the adjacent

cuticle and proximal and/or lateral nail folds (Hutchinson’s

sign)

• F – Family history

If melanoma or another serious condition is suspected, nail

matrix biopsy is recommended for diagnosis Traditional

biopsy techniques should be considered, provided they yield

an adequate tissue sample.2,11 Treatment should be directed

towards the underlying cause of the melanonychia If the

melanonychia is suspected to be drug-induced, removal of the

offending drug may be necessary, if medically feasible

Figure 10 2: (A and B) Benign longitudinal melanonychis

10 Hyperpigmented Disorders • Confluent and reticulated papillomatosis of Gougerot and Carteaud

10 Quinlan KE, Janiga JJ, Baran R, Lim HW Transverse melanonychia secondary to total skin electron beam therapy: a report of 3 cases

J Am Acad Dermatol 2005; 53(2 Suppl 1):S112–S114.

11 Bormann G, Marsch WC, Haerting J, Helmbold P Concomitant traumas influence prognosis in melanomas of the nail apparatus Br J Dermatol 2006; 155(1):76–80.

6 Kopf A, Waldo E Melanonychia striata Aust J Dermatol 1980;

21:59–70.

7 André J, Lateur N Pigmented nail disorders Dermatol Clin 2006;

24(3):329–339.

8 Levit EK, Kagen MH, Scher RK, Grossman M, Altman E The ABC rule

for clinical detection of subungual melanoma J Am Acad Dermatol

2000; 42(2 Pt 1):269–274.

9 Baran R, Kechijian P Longitudinal melanonychia (melanonychia

striata): diagnosis and management J Am Acad Dermatol Dec 1989;

Gougerot and Carteaud described this dermatologic condition

in the early part of the twentieth century It was first labeled

‘papillomatose pigmenteé innominée’ and then ‘confluent

and reticular papillomatosis’ became the widely accepted

term.1 Lesions are characterized by hypochromic or blue-gray

papules which coalesce and become confluent in the center

with a reticular pattern in the periphery Lesions are typically located in the epigastrium and inframammary areas (Fig 10.3) However, they may involve the neck, shoulders and pubic area in advanced cases.2,3 The disease has shown no gender or racial predilection.4 Electron microscopy imaging has shown a defect of keratinization, a granular layer decrease and associated hypermelanosis.5

The etiology of CRPGC etiology is unknown, but theories abound Since response to antifungal agents has been docu-

mented, heavy colonization with Pityrosporum orbiculare has

been theorized as the causative agent.6,7 Several antibiotics have also been effective, and their anti-inflammatory proper-ties have been thought to be the responsible mechanism of action.8 Others have posited abnormal keratinization as a factor, and this is supported by the histopathologic findings mentioned above.9 A propensity towards obesity and an endo-crinopathy have been observed anomalies.10 Finally, genetics may play a role.11

Figure 10 3: (A and B) Confluent and reticulated papillomatosis

cases, response to this agent and to other medications, both antifungal and keratolytic, were variable.

Confluent and reticulated papillomatosis: response to otene Bowman P, Davis LS J Am Acad Dermatol 2003;

tazar-48(5):S80–S81

Case report of an 11-year-old Black girl with confluent and reticulated papillomatosis who was treated with tazarotene gel The treatment was well tolerated and the patient cleared completely

Six cases of confluent and reticulated papillomatosis ated by various antibiotics Jang HS, Oh CK, Cha JH, Cho

allevi-SH, Kwon KS J Am Acad Dermatol 2001; 44(4):652–655.This study reports 6 cases of CRP alleviated by various antibiotics The patient described in case 1 is a 16-year-old girl whose disease was alleviated by oral minocycline, 100 mg daily for 8 weeks Cases 2 and 3 describe an 18-year-old woman and a 17-year-old male adolescent whose disease was reduced by oral fusidic acid, 1000 mg daily for 4 weeks Case

4 describes a 14-year-old girl who received oral clarithromycin,

500 mg daily for 5 weeks Case 5 describes a 22-year-old woman whose disease was reduced by oral erythromycin,

1000 mg daily for 6 weeks Case 5 reports a 24-year-old man who received oral azithromycin, 500 mg daily 3 times per week for 3 weeks Complete clearing after treatment with the above mentioned antibiotics was reported

3 Ferreira LM, Diniz LM, Ferreira CJ Confluent and reticulated lomatosis of Gougerot and Carteaud: report of three cases An Bras Dermatol 2009; 84(1):78–81.

papil-4 Scheinfeld N Confluent and reticulated papillomatosis: a review of the literature Am J Clin Dermatol 2006; 7:305–313.

5 Lee SH, Choi EH, Lee WS, et al Confluent and reticulated tosis: a clinical, histopathological, and electron microscopic study

papilloma-J Dermatol 1991; 18:725–730.

6 Hamaguchi T, Nagase M, Higuchi R, Takiuchi I A case of confluent and reticulated papillomatosis responsive to ketoconazole cream Nippon Ishinkin Gakkai Zasshi 2002; 43:95–98.

7 Roberts SO, Lachapelle JM Confluent and reticulate papillomatosis (Gougerot–Carteaud) and pityrosporum orbiculare Br J Dermatol 1969; 81:841–845.

8 Chang SN, Kim SC, Lee SH, Lee WS Minocycline treatment for ent and reticulated papillomatosis Cutis 1996; 57:454–457.

conflu-9 Carrozzo AM, Gatti S, Ferranti G, et al Calcipotriol treatment of fluent and reticulated papillomatosis (Gougerot–Carteaud syndrome)

con-J Eur Acad Dermatol Venereol 2000; 14:131–133.

10 Koizumi N, Hatamochi A, Shinkai A Confluent and reticulated lomatosis was improved by treatment with minocycline hydrochlo- ride: report of two cases Rinsho Derma 2002; 44:63–637.

papil-11 Inalöz HS, Patel G, Knight AG Familial confluent and reticulated papillomatosis Arch Dermatol 2002; 138:276–277.

Confluent and reticulated papillomatosis: response to

minocycline Montemarano AD, Hengge M, Sau P, Welch M

J Am Acad Dermatol 1996; 34:253–256

The objective of this study was to evaluate the effectiveness

of oral minocycline in 9 patients with CRP These subjects were

treated with oral minocycline 50 mg twice a day, for 6 weeks

The average follow-up period was 11 months Recurrence rate,

side effects, and effectiveness of therapy were assessed All

patients except two had a 90–100% response to therapy

Recur-rences were noted in 3 patients, all of whom responded to

re-treatment with minocycline None of the 9 patients had an

adverse reaction Minocycline 50 mg twice a day is safe and

effective for treatment of CRP

Confluent and reticulated papillomatosis was improved by

treatment with minocycline hydrochloride: report of two

cases Koizumi N, Hatamochi A, Shinkai A Rinsho Derma

2002; 44:63–67

An 18-year-old male and a 12-year-old female with CRPGC,

both obese, responded to treatment with minocycline

Treatment of confluent and reticulated papillomatosis with

azithromycin Atasoy M, Ozdemir S, Aktas¸ A, Aliagˇaogˇlu C,

Karakuzu A, Erdem T J Dermatol 2004; 31:682–686

This is the case of a 21-year-old male patient with confluent

and reticulated papillomatosis initially treated with

ketocona-zole cream for 2 weeks without improvement The patient

demonstrated a significant response to treatment with

azithromycin

A case of confluent and reticulated papillomatosis

respon-sive to ketoconazole cream Hamaguchi T, Nagase M, Higuchi

R, Takiuchi I Nippon Ishinkin Gakkai Zasshi 2002; 43:

95–98

A case report of a patient responding to ketoconazole

cream, as fungal spores were found in the skin

Confluent and reticulated papillomatosis responsive to

sele-nium sulfide Nordby CA, Mitchell AJ Int J Dermatol 1986;

25:194–199

Case report of CRP that showed a significant therapeutic

response to topical selenium sulfide In previously described

10 Hyperpigmented Disorders • Drug-induced pigmentation

Figure 10 4: Drug-induced pigmentation resulting from chloroquine (Courtesy of

Neil Fenske, MD, Tampa, FL; From Callen, Color Atlas of Dermatology, 2e,

copyright Elsevier 1999 )

Drug-induced

pigmentation

Exposure to a wide range of pharmacologic agents can induce

clinically significant pigmentary changes Though these

changes are typically benign, the cosmetic effects can have a

severe psychological impact on affected individuals, especially

on those with darker skin (Fig 10.4).1

Three classes of drug-induced pigmentary changes have

been described:2

• hyperpigmentation/melanosis

• hypopigmentation/leukoderma

• dyspigmentation

Pharmacologically related cutaneous changes are fairly

common as 10–20% of all cases of hyperpigmentation are

attributed to drug reactions.3 Drug reactions have been strongly

associated with specific drugs and/or classes of drugs:

• enhanced melanin production

• cutaneous drug-induced post-inflammatory changes

• reduced number of skin melanocytes

• enzymatic blockade of melanogenesis

• inhibition of melanosome transfer

Table 10.1 describes the particular cutaneous tions of common medications Cutaneous manifestations are specific to each drug.4

manifesta-The effect of the antimalarial chloroquine on the tary system has been well described This medication appears to bind to melanin and becomes concentrated

pigmen-in melanpigmen-in-contapigmen-inpigmen-ing structures

The popular antibiotic, minocycline, can lead to diffused pigmentary changes which have been categorized into three types:

• Type I – blue-black/gray pigment on the face in areas of scarring or inflammation associated with acne

• Type II – blue-gray pigment on normal skin on the shins and forearms

• Type III – diffuse muddy-brown discoloration in areas of sun exposure

According to Geria et al, Types I and II will resolve over time while type III seems to be permanent.5 Treatment is outlined below A complete history and physical examination will typically elucidate the diagnosis with a biopsy reserved for equivocal cases

Discontinuation of the offending agent is the sine qua non

of this condition Reassurance of the (usually) temporal nature

of the event is also important Use of sunscreen to prevent progression is recommended as the combination of sunlight and certain drugs may exacerbate the condition Finally, laser therapy is useful in selected cases

First-Line Therapies

Q-switched alexandrite laser D

Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched alexandrite laser Alster TS, Gupta SN

Dermatol Surg 2004: 30(9):1201–1204

6 patients with minocycline-induced hyperpigmentation

on the face or legs were treated with a Q-switched alexandrite laser on a bimonthly basis until pigmentation was eradicated Cutaneous pigmentation resolved completely in all patients in

an average of four laser sessions Side effects were limited to transient purpura and mild desquamation without scarring or dyspigmentation

Table 10 1 Cutaneous manifestations of common offending agents

Drug/drug group Clinical features

Phenytoin • 10% of patients develop pigmentation of the

face and neck resembling chloasma (clearly defined, roughly symmetrical dark brown patches)

• Fades after a few months when drug has been stopped

Antimalarials • About 25% of patients receiving chloroquine

or hydroxychloroquine for several years develop bluish-gray pigmentation on face, neck and sometimes lower legs and forearms

• Continuous long-term use may lead to blue-black patches, especially in sun-exposed areas

• Nail bed and corneal and retinal changes may also develop

Cytotoxic drugs • Busulfan, cyclophosphamide, bleomycin and

adriamycin have all produced hyperpigmentation to some degree

• Banded or diffuse pigmentation of nails often occurs

Amiodarone • Blue-gray pigmentation in sun-exposed

areas (face and hands)

• Photosensitivity occurs in 30–57% of patients whilst 1–10% show skin pigmentation

• Skin pigmentation is reversible but may take

up to 1 year for complete resolution after the drug has been stopped

NSAIDs • Often associated with fixed drug eruptions

(drugs that cause a single or few sharply demarcated erythematous lesions which resolve promptly but leave a local brown pigmentation)

• May occur on the face, extremities and genitalia

Laser treatment of imipramine-induced hyperpigmentation

Atkin DH, Fitzpatrick RE J Am Acad Dermatol 2000; 43(1 Pt 1):77–80

One patient with significant imipramine- (a tricyclic antidepressant) induced pigmentation underwent treatment with carbon dioxide, erbium, alexandrite, and ruby lasers on hyperpigmented areas Biopsies were performed before treat-ment, immediately after treatment, and at clearing with the alexandrite laser The Q-switched alexandrite and ruby lasers resulted in clinical improvement in the patient’s hyper-pigmentation and a decrease in pigment granules on light microscopy

Amiodarone-induced skin pigmentation: Q-switched laser therapy, an effective treatment option Wiper A, Roberts DH,

Schmitt M Heart 2007; 93(1):15

Case report of successful treatment of amiodarone-induced hyperpigmentation using a Q-switched ruby laser on a 48-year-old man

Commonly encountered pitfallsDrug induced hyperpigmentation can be confused with a variety of dermatoses This may lead to a delay in both diag-nosis and discontinuation of the offending medication The consequences of mis diagnosis can be particularly deleterious

as drug-induced pigmentation may be permanent

Special management & counseling considerations

If possible, the causative agent should be immediately discontinued

Patients should be informed that drug induced mentation may be permanent Pigmentation caused by amio-darone, for example, may require one year to resolve

hyperpig-The use of sunscreen, sun avoidance and protective clothing can help ameliorate the condition

[Acc-3 Dereure O Drug-induced skin pigmentation: epidemiology, diagnosis and treatment Am J Clin Dermatol 2001; 2(4):253–262.

4 Dermnet NZ Photosensitivity http://www.dermnetnz.info/reactions/ photosensitivity.html [accessed August 25, 2009].

5 Geria AN, Tajirian AL, Kihiczak G Minocycline-induced skin tation: an update Acta Dermatovenerol Croat 2009; 17(2):123–126.

pigmen-10 Hyperpigmented Disorders • Erythema dyschromicum perstans

Figure 10 5: Erythema dyschromicum perstans Numerous oval to polygonal,

gray-brown macules on the lower extremities (Courtesy of Wake Forest University;

from Bolognia, Dermatology, 2e, copyright Elsevier 2008 )

Erythema

dyschromicum

perstans

Erythema dyschromicum perstans (EDP) was first described in

1957 C Oswaldo Ramirez of San Salvador, El Salvador,

referred to patients with this disease as Los cenicientos, which

is Spanish for “the ashen ones”.1 EDP was later named

derma-tosis ceniciento which directly translates to ashy dermaderma-tosis

This name refers to the blue-gray hyperpigmented macules

that characterize the disease.1 These hyperpigmented macules

usually erupt on the face, neck (Fig 10.5), trunk and arms as

oval, polycyclic, or irregularly shaped At onset the macules

appear gray in color with an occasional erythematous or

ele-vated border There are no known systemic symptoms or

associations

The etiology of EDP is unknown but several theories

abound Some authors consider it to be a variation of lichen

planus actinicus.2 Other authors have considered the

geo-graphic distribution of EDP and suggested environmental

factors as the etiology However, all attempts to identify

pollutants within the geographic distribution have been

unsuccessful

EPD is prevalent in darker-skinned adults, particularly

those of Hispanic decent.3 In contrast, most children with EDP

have fair-skin.4

In 2007, a study was published in which histocompatibility

complexes in Mexican Mestizo patients were analyzed.5

Researchers found that HLA-DR4 was the most commonly

associated complex in individuals with EDP, 65% versus

23% for a control group, which lends credence to a genetic

as stimulating phagocytosis and release of lysosomal enzymes.6

Clinical trial with clofazimine for treating erythema chromicum perstans Evaluation of cell-mediated immunity

dys-Piquero-Martín J, Pérez-Alfonzo R, Abrusci V, et al Int J matol 1989; 28(3):198–200

Der-Eight patients with erythema dyschromicum perstans (EDP), treated with clofazimine, had T-helper/T-suppressor cytotoxic ratio (CD-4/CD-8) and in vitro lymphoproliferative response on stimulation with phytohemaglutin (PHA) and concanavalin A (Con A) analyzed pre- and post-treatment Seven of the 8 patients had excellent to good responses A significant change in the CD-4/CD-8 ratio was observed in the immunologic evaluation after treatment A decreased response

to PHA, and no change in the response to Con A was noted Clofazimine produced a favorable cosmetic result and induces changes in cell-mediated response

Involvement of cell adhesion and activation molecules in the pathogenesis of erythema dyschromicum perstans (ashy dermatitis) Baranda L, Torres-Alvarez B, Cortes-Franco R,

et al Arch Dermatol 1997; 133(3):325–329

Using a immunohistochemical technique, the expression of cell adhesion and activation molecules was assessed in skin biopsy samples obtained from 6 patients with erythema dys-chromicum perstans The skin biopsies were obtained before and after 3 months of clofazimine therapy (100 mg daily) Our results suggest that some cell adhesion and activation mole-cules are involved in the pathogenesis of erythema dyschromi-cum perstans Clofazimine appears to have an important effect

on the inflammatory phenomenon of erythema cum perstans

dyschromi-Erythema dyschromicum perstans: response to dapsone therapy Bahadir S, Cobanoglu U, Cimsit G, Yayli S, Alpay K

Int J Dermatol 2004: 43(3);220–222

Various treatments have been used for EDP but without benefit, including sun protection, chemical peels, antibiotics, corticosteroids, vitamins, isoniazid, griseofulvin, and chloro-quine The authors support the efficacy of clofazimine and dapsone The authors report a case of EDP that responded remarkably well to treatment with dapsone

one of the few effective oral agents used to treat EDP has a serious adverse event profile They include ichthyosis and fatal enteropathy Therefore, topical steroids, phototherapy or lasers should be utilized before clofazimine.

Since the prognosis differs according to age, and the tion tends to remit spontaneously in pre-pubertal children (but not in adults), treatment is often unnecessary in this population.7

4 Torrelo A, Zaballos P, Colmenero I, Mediero IG, de Prada I, Zambrano

A Erythema dyschromicum perstans in children: a report of 14 cases

J Eur Acad Dermatol Venereol 2005; 19(4):422–426.

5 Correa MC, Memije EV, Vargas-Alarcon G, et al HLA-DR association with the genetic susceptibility to develop ashy dermatosis in Mexican Mestizo patients J Am Acad Dermatol 2007; 56(4):617–620.

6 Arbiser JL, Moschella SL Clofazimine: a review of its medical uses and mechanisms of action J Am Acad Dermatol 1995; 32(2 Pt 1):241– 247.

7 Silverberg NB, Herz J, Wagner A, et al Erythema dyschromicum perstans in prepubertal children Pediatr Dermatol 2003; 20(5): 398–403.

Erythema dyschromicum perstans: response to dapsone

therapy Kontochristopoulos G, Stavropoulos P, Pantelos D

Int J Dermatol 1998; 37:790–799

This study reports two cases of EDP that responded well to

dapsone In the first case, dapsone at 100 mg daily for 12

weeks resulted in regression of the active borders and central

hyperpigmentation No new lesions developed In the second

case, treatment with dapsone 100 mg produced a significant

decrease in hyperpigmentation after 8 weeks and new lesions

did not appear However, discontinuation of therapy resulted

in the recurrence of the eruption, which disappeared when

dapsone was reinstituted

Commonly encountered pitfalls

The differential diagnosis of EDP as with many pigmentary

disorders, includes a drug eruption A detailed history must be

taken to identify concomitant medications A biopsy will

dis-tinguish between a drug eruption as well as lichen planus, as

some theorize that EDP is a variant of lichen planus

Addition-ally, systemic conditions that have similar cutaneous

presenta-tions such as Addison’s disease and hemochromatosis should

not be overlooked

Special management & counseling considerations

While EDP is a benign disorder, treatment presents special

management and counseling considerations Clofazimine,

Exogenous ochronosis

Exogenous ochronosis (EO) is characterized by a bluish facial

pigmentation resulting from the application of hydroquinone

(HQ) First described in 1906, the etiology of EO is unknown,

although it is postulated that HQ inhibits homogentisic acid

oxidase, which leads to the development of ochronotic

pigment (Fig 10.6).1,2,3

The etiology of EO is unknown, however several theories

exist.1 Hydroquinone (HQ) may inhibits homogentesic acid

oxidase in the dermis, leading to the development of dark

pigment or ochronotic pigmentation.2

EO typically occurs in dark skinned individuals; however,

it has been reported in Caucasians and Hispanics Clinical

signs of ochronosis are enumerated in Box 10.1 While HQ is

foremost in causing EO, several agents can also cause the

con-dition; these include antimalarials and products with mercury,

picric acid and phenol.3

The Hull and Procter study illustrates that unlike many

other pigmentary disorders, the pathogenesis of EO requires

functioning melanocytes A biopsy of a patient with

ochrono-sis and vitiligo, showed no melanocytes in the vitiliginous area

and ochronotic pigment in the areas with EO.4 Figure 10 6: Distribution of exogenous ochronosis of the cheeks

First-Line Therapies

Removal of the offending agent

10 Hyperpigmented Disorders • Exogenous ochronosis

Exogenous ochronosis Snider RL, Thiers BH J Am Acad

Der-matol 1993; 28:662–664

Snider and Thiers reported a case of exogenous ochronosis

in a 59-year-old black woman who has a 5-year history of

progressive darkening of the skin around her eyes She had

been using 2-percent hydroquinone skin bleaching cream

once daily for many years About 9 months before the

exami-nation she has used 3-percent hydroquinone twice daily for 3

months, then 4-percent hydroquinone with a sunscreen twice

daily for 3 months Examination showed numerous pinpoint

blue-black spots around the eye area A biopsy specimen

revealed multiple scattered, elongted, curved, and oval

depos-its of ochronotic pigment within the collagen bundles

of products with high concentrations of hydroquinone which

is seemingly the case with African patients Patients emigrating from Africa who present with facial dyspigmentation should

be evaluated for exogenous ochronosis In the United States, the majority of cases of exogenous ochronosis are a result of the prolonged use of hydroquinone-containing products of low concentrations (1–2%) Physicians should ask patients about their use of low-dose hydroquinone-containing products

Exogenous ochronosis may be mistaken for the pigmentary disorders melasma or post-inflammatory hyperpigmentation and therapy with the causative agent, hydroquinone initiated

A thorough history of over-the-counter or prescription quinone use must be obtained Furthermore, eliciting a history

hydro-of initial improvement in pigmentation with hydroquinone therapy with subsequent worsening is supportive of the diag-nosis of exogenous ochronosis

Special management & counseling considerationsDiagnosis of the majority of pigmentary disorders is clinical and does not require a skin biopsy However, given the diffi-culty of diagnosing exogenous ochronosis, it may be appropri-ate to perform a skin biopsy early to confirm the diagnosis.Patients with pigmentary disorders, including exogenous ochronosis, are reluctant to discontinue hydroquinone-containing products Therefore, the importance of educating these patients that hydroquinone causes the problem, and must be permanently discontinued, cannot be overempha-sized Furthermore, patients must be made aware that this pigmentation may be permanent

References

1 Touart DM, Sau P Cutaneous deposition diseases Part II J Am Acad Dermatol 1998; 39:527–546.

2 Burkhart CG, Burkhart CN Ochronosis Emedicine Specialties 1998.

3 Huerta Brogeras M, Sanchez-Viera M Exogenous ochronosis J Drugs Dermatol 2006; 5:80–81.

4 Hull RB, Procter PR The melanocyte: an essential link in induced ochronosis J Am Acad Dermatol 1990; 22:529–531.

hydroquinone-Box 10 1 Clinical signs of ochronosis

• Stage 1: Erythema and macular pigmentation

• Stage 2: Darker pigmentation, papules and atrophy

• Stage 3: Papulonodular, granulomatous or annular lesions

Probable coexisting exogenous ochronosis and mercurial

pigmentation managed by dermabrasion Lang PG J Am

Acad Dermatol 1988; 19:942–946

A patient with blue-gray discoloration of the face is described

who used bleaching creams containing mercury and

hydro-quinone for many years Biopsy showed deposits that were

compatible with both mercury deposition and exogenous

ochronosis Dermabrasion was successfully employed to

remove these deposits

Hydroquinone-induced localized exogenous ochronosis

treated with dermabrasion and CO 2 laser Diven DG, Smith

EB, Pupo RA, Lee M J Dermatol Surg Oncol 1990;

16:1018–1022

Localized exogenous ochronosis can result from the

repeated use of hydroquinone-containing creams, many of

which are available over the counter This is a case that was

managed by dermabrasion and CO2 laser The incidence and

Figure 10 7: Gingival hyperpigmentation Racial pigmentation of the gums

(From Johnson, Moy, White: Ethnic Skin – Medical and Surgical, Mosby Inc ,

copyright Elsevier 1998 )

Gingival

hyperpigmentation

Few dermatoses can cause as much embarrassment and

psy-chological damage as gingival hyperpigmentation Abnormal

melanocyte activity results in deposition of melanin in the

basal layer and hyperpigmentation and discoloration of the

gingiva.1,2 The causes of gingival hyperpigmentation include

the following,3,4 (Fig 10.7)

Dark skinned individuals and those of African, Asian, and

Latino ancestry are genetically prone to exhibit gingival

hyper-pigmentation.5,6 Interestingly, fair skinned individuals, despite

having approximate numbers of gingival melanocytes, will not

express the condition.7

Treatment of gingival hyperpigmentation by erbium-doped, yttrium, aluminum, and garnet laser for esthetic purposes

Azzeh MM J Periodontol 2007; 78:177–184

In this clinical study, 6 White subjects with dark-brown to black gingival hyperpigmentation (3 of whom were smokers) were treated with the Er:YAG laser (settings: 250 mJ, 15 Hz, using the defocused mode) without using anesthesia Each subject was initially treated for 20–25 minutes and then underwent the same treatment 4 days later (same settings) With each treatment there were no signs of complications All wounds healed almost completely within the 4-day period prior to the second treatment Follow-up visits were performed 6–18 months later There were no signs of recurrence in the 6 subjects

Treatment of gingival hyperpigmentation for esthetic poses by Nd:YAG Laser: report of 4 cases Atsawasuwan P,

pur-Greethong K, Nimmanon V Periodontol 2000; 71:315–321

In this study, 4 subjects with gingival hyperpigmentation were treated with the Nd:YAG laser (settings: 6 watts, 60 mJ,

100 pulses per second, 320 µm diameter fiber optic piece) There were no complications Complete ablation of the hyperpigmented areas was achieved in all subjects Follow-up

hand-at 3–4 weeks then 11–13 months post procedure found the gingiva to be healthy, pink, and firm

Gingival melanin pigmentation and its treatment with the

CO 2 laser Erdogan O, Esen E, Haytac MC, Karsli ED, Oz IA

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98:522–527

10 subjects with gingival melanin pigmentation were treated using superpulsed CO2 laser (settings: 10 watts, 0.8 mm spot size, 20 Hz, 10 milliseconds) Pigmented areas were measured on pre- and post-operative standard digital images

by the aid of image-analyzing software Statistical analysis of

the data was performed by Mann Whitney U test Ablation of

the hyperpigmented gingiva was accomplished with minimal carbonization and almost no bleeding Post-operative healing was uneventful Two cases of partial repigmentation were observed during 24-month follow-up Statistical analysis of the data revealed a significant difference between pre- and post-operative measurements of pigmented area

Commonly encountered pitfallsThe differential diagnosis of gingival hyperpigmentation

is quite varied and includes both benign and malignant conditions Conditions associated with malignancy including Peutz–Jeghers syndrome, oral melanoacanthoma and melanoma Gingival tattooing is a phenomenon seen in certain cultures, thus it is important to obtain a tattoo history.9

10 Hyperpigmented Disorders • Melasma

3 Leston JM, Santos AA, Varela-Centelles PI, Garcia JV, Romero MA, Villamor LP Oral mucosa: variations from normalcy, Part II Cutis 2002; 69(3):215–217.

4 Dummett CO, Sakumura JS, Barens G The relationship of facial skin complexion to oral mucosa pigmentation and tooth color J Prosthet Dent 1980; 43(4):392–396.

5 Fry L, Almeyda JR The incidence of buccal pigmentation in caucasoids and negroids in Britain Br J Dermatol 1968; 80(4):244–247.

6 Tamizi M, Taheri M Treatment of severe physiologic gingival tation with free gingival autograft Quintessence Int 1996; 27(8): 555–558.

pigmen-7 Esen E, Haytac MC, Oz IA, Erdogan O, Karsli ED Gingival melanin pigmentation and its treatment with the CO 2 laser Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98(5):522–527.

8 Hoexter DL Periodontal aesthetics to enhance a smile Dent Today 1999; 18(5):78–81.

9 Rawal SY, Burrell R, Hamidi CS, et al Diffuse pigmentation of lary attached gingiva: four cases of the cultural practice of gingival tattoo J Periodontol 2007; 78(1):170–176.

maxil-Special management & counseling considerations

Cessation of smoking or discontinuation of an offending

agent can reverse hyperpigmentation in many cases A visit

from a patient experiencing smoker’s melanosis would be a

very opportune time to initiate smoking cessation counseling

Gingival hyperpigmentation can cause embarrassment in

patients with large gum lines or a ‘gummy smile’; these patients

should be offered treatment options

Melasma is characterized by symmetrical hyperpigmented

patches that vary from light to dark brown in color The lesions

are caused by both dermal and epidermal melanin deposition

This differentiation is critically important when assessing

treat-ment outcomes as dermal melasma is much more difficult to

ameliorate (Table 10.2) With clinical examination alone, it is

difficult to differentiate between the different types of melasma

Historically, Wood’s light examination was used for patients

with Fitzpatrick skin types I–IV to distinguish and highlight

changes of epidermal melasma However, recent data indicate

that skin biopsy is required to distinguish between types of

melasma as the Wood’s light may be inconclusive

Individuals with melasma display an exaggerated response

to UV light.1 Photosensitizing drugs, autoimmune thyroid

dis-orders, cosmetics and hormone therapy have all been linked

to melasma

The condition primarily affects women, particularly during pregnancy or while using oral contraceptives.2 During preg-nancy it is referred to as ‘melasma gravidarum’ or ‘mask of pregnancy’ and has been reported in up to 80% of pregnant Mexican females Melasma can also occur in men.3

There are three recognized patterns of melasma (Table 10.3):

• Centrofacial, involving the cheeks, forehead, upper lips, nose and chin (accounting for 63% of the cases in one study);

• Malar, involving the cheeks and nose (21%);

• Mandibular, involving the mandible (16%) (Figs 10.8, 10.9).4

Table 10 2 Clinical features of melasma6

Type of melasma Clinical features

Epidermal • Well-defined border

• Dark brown color

• Appears more obvious under Woods light

• Responds well to treatmentDermal • Ill-defined border

• Light brown color

• Unchanged under Woods light

• Responds poorly to treatmentMixed • Combination of light and brown patches

• Partial improvement with treatment

Figure 10 8: Male with Melasma

The incidence of melasma is thought to be higher in patients

with Fitzpatrick skin types V and VI It is especially common

in Hispanics, African-Caribbeans and Asians It is much more

prevalent in people who live in areas of intense UV exposure,

e.g Southeast Asia.5,6

Figure 10 9: Female with Melasma

First-Line Therapy

A double-blind, comparative, placebo-controlled study of

the efficacy and tolerability of 4% hydroquinone as a

depigmenting agent in melasma Ennes SBP, Paschoalick RC,

Mota De Avelar Alchorne M J Dermatolog Treat 2000;

11:173–179

A total of 48 patients were randomly selected with 24

receiving hydroquinone 4%, and 24 placebo Patients were

instructed to use and apply additional sunscreen The 12-week

treatment period focused on evaluation of efficacy and

toler-ability with photographic assessment every 3 weeks Efficacy

was classified into three categories: total improvement,

partial improvement, or failure Tolerability was classified as

excellent, good, fair or poor Results showed a statistically

significant difference between the efficacy of the hydroquinone

4% and placebo group In the hydroquinone group, 40% of

the patients showed complete disappearance of spots at the

end of the treatment and there were no therapeutic failures

reported In the placebo group, 10% of the patients showed

total improvement, while therapeutic failures occurred in 20%

Table 10 3 Characteristics of melasma

• Symmetrical facial hyperpigmentation

• Central facial distribution (most common)

• Malar distribution

• Mandibular distribution (least common)

• Can occur in non-facial sun exposed areas

• Increased melanin production but normal number of melanocytes

• May involve epidermis, dermis or both

• More common in women with Fitzpatrick skin type V and VI

• Exacerbated by sun exposure, pregnancy and oral contraceptives

of the patients Both treatments were well tolerated, with no serious adverse events reported

Efficacy and safety of a new triple-combination agent for the treatment of facial melasma Taylor SC, Torok H, Jones T,

et al Cutis 2003; 72:67–72

The primary objective of two 8-week, multicenter, mized, investigator-blind studies was to compare the efficacy and safety of a hydrophilic cream formulation containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone aceto-nide 0.01% (RA + HQ + FA), with the dual-combination agents tretinoin plus hydroquinone (RA + HQ), tretinoin plus fluoci-nolone acetonide (RA + FA), and hydroquinone plus fluoci-nolone acetonide (HQ + FA) All agents had the same drug concentration and vehicle A total of 641 adult patients, pre-dominantly female, with Fitzpatrick skin types I through IV and moderate to severe melasma were randomized The primary efficacy analysis involved the proportion of intent-to-treat patients in each treatment group whose condition had completely cleared by week 8 Both studies demonstrated that significantly more of the patients treated with RA + HQ + FA (26.1%) experienced complete clearing compared with the other treatment groups (4.6%) at the end of week 8 (p < 0001) In addition, at week 8, a 75% reduction in melasma/pigmentation was observed in more than 70% of patients treated with RA + HQ + FA compared with 30% in patients treated with the dual-combination agents Erythema, skin peeling, burning, and/or stinging sensation were among the most common adverse reactions The majority of treatment-related adverse events were of mild severity

rando-Community-based trial of a triple-combination agent for the treatment of facial melasma Grimes P, Kelly AP, Torok

H, Willis I Cutis 2006; 77(3):177–184

This was a phase IV community-based trial with 1290 jects with moderate to severe melasma and a Fitzpatrick skin type of I–VI The efficacy parameters were the Melasma Area and Severity Index (MASI) score which was found to decrease significantly at weeks 4 and 8 compared with baseline in the overall study population (p < 0.001) By week 8, investigator global evaluations showed that 75% of patients had moderate

sub-or marked improvement sub-or were almost clear sub-or clear (p < 0.001)

10 Hyperpigmented Disorders • Melasma

This 10-month, randomized, vehicle-controlled clinical

trial investigated the efficacy of topical 0.1% all-trans retinoic

acid (tretinoin) in the treatment of melasma in black patients

28 of 30 black patients with melasma completed the study in which they applied either 0.1% tretinoin or vehicle cream daily to the entire face They were evaluated clinically using MASI (Melasma Area and Severity Index), colorimetrically, and histologically After 40 weeks, there was a 32% improvement

in the MASI score in the tretinoin treatment group compared with a 10% improvement in the vehicle group Colorimetric measurements showed lightening of melasma after 40 weeks

of tretinoin treatment vs vehicle Lightening of melasma, as determined clinically, correlated well with colorimetric meas-urements Histologic examination of involved skin revealed a significant decrease in epidermal pigmentation in the tretinoin group compared with the vehicle group Side effects were limited to a mild ‘retinoid dermatitis’ occurring in 67% of tretinoin-treated patients This controlled study demonstrates that topical 0.1% tretinoin lightens melasma in Black patients, with minimal side effects

Topical tretinoin (retinoic acid) improves melasma A vehicle-controlled, clinical trial Griffiths CE, Finkel LJ, Ditre

CM, Hamilton TA, Ellis CN, Voorhees JJ Br J Dermatol 1993; 129(4):415–421

This randomized, vehicle-controlled study, enrolled 38 women to one of two treatment groups: 0.1% tretinoin (n = 19) or vehicle cream (n = 19) once daily to the face for 40 weeks At the end of treatment 13 (68%) of 19 tretinoin-treated patients were clinically rated as improved or much improved, compared with 1 (5%) of 19 in the vehicle group (p = 0.0006) After 24 weeks of tretinoin treatment significant improvement was first apparent Colorimetry (an objective measure of skin colour) demonstrated a 0.9 unit lightening of tretinoin-treated melasma and a 0.3 unit darkening with vehicle (p = 0.01); these results correlated with clinical lighten-ing (r = 0.55, p = 0.0005) Histologically, epidermal pigment was reduced by 36% following tretinoin treatment, compared with a 50% increase with vehicle (p = 0.002) Reduction in epidermal pigment also correlated with clinical lightening (r = −0.41, p = 0.01) Moderate cutaneous side effects of ery-thema and desquamation occurred in 88% of tretinoin-treated and 29% of vehicle-treated patients Results concluded that topical 0.1% tretinoin produces significant clinical improve-ment of melasma, mainly due to reduction in epidermal pigment, but improvement is slow

Melasma Kauh YC, Zachian TF Adv Exp Med Biol 1999;

455:491–499

In this study, 40 Korean women were placed in an open label study using 0.1% retinoic acid in combination with 3% hydroquinone The results rated the treatment as excellent or good improvement 96% of the subjects had mild to moderate reaction to treatment

Adapalene in the treatment of melasma: a preliminary report Dogra S, Kanwar AJ, Parsad D J Dermatol 2002;

29(8):539–540

The combination of glycolic acid peels with a topical

regimen in the treatment of melasma in dark-skinned

patients: a comparative study Sarkar R, Kaur C, Bhalla M,

Kanwar AJ Dermatol Surg 2002; 28:828–832

The purpose of this comparative study was to determine if

serial glycolic acid peels provide additional improvement

when combined with a time-tested topical regimen, a

modifi-cation of Kligman’s formula (hydroquinone 5%, tretinoin

0.05%, hydrocortisone acetate 1% in a cream base) All

recruited subjects had epidermal melasma as detected by

Wood’s light examination 40 melasma patients of Indian

descent were divided into two groups of 20 each One group

received serial glycolic acid peel combined with a topical

regimen, modified Kligman’s formula The control group

received modified Kligman’s formula alone The results were

evaluated by a clinical investigator both subjectively and with

photographs taken at baseline, 12 (before the fourth peel),

and 21 (3 weeks after the sixth peel) weeks For clinical

evalu-ation, the Melasma Area and Severity Index (MASI) was used

Results showed a significant decrease in the MASI score from

baseline to 21 weeks in both groups (p < 001) The group

receiving the glycolic acid peels showed a trend toward more

rapid and greater improvement, with statistically significant

results (p < 001) Only a few side effects were observed in the

peel group This study demonstrates that serial glycolic acid

peels provide an additional effect to a topical regimen which

is a modification of the time-tested Kligman’s regimen for

treating melasma in dark-complexioned individuals, if used

judiciously and under supervision

A comparison of triple combination cream and

hydroqui-none 4% cream for the treatment of moderate to severe

facial melasma Cestari TF, Hassun K, Sittart A, Viegas ML

Presented as a poster at the 63rd Annual Meeting of the

American Academy of Dermatology New Orleans, February

18–22, 2005

The goal of this study was to compare the efficacy and safety

of a triple combination (TC) cream and monotherapy with 4%

hydroquinone (HQ) cream in the treatment of moderate to

severe facial melasma 120 patients were enrolled to one of

two groups: TC cream once daily or HQ cream twice daily for

8 weeks Evaluations included static global severity assessment

of melasma, improvement of melasma over time, local

toler-ability, and adverse events TC cream was significantly more

effective than HQ cream from week 4 onwards: lesions were

approximately equivalent to the surrounding skin in 35% of

all TC-treated patients, compared to 5% of those who used

HQ cream (p = 0.0001) Improvement of more than 75% was

achieved by 73% of TC cream patients and 49% of HQ cream

patients (p = 0.007) Both groups reported similar adverse

events, which included erythema, burning sensation, and

desquamation Results concluded that TC cream was more

effective than the HQ cream for the treatment of moderate to

severe facial melasma

Topical retinoic acid (tretinoin) for melasma in black

patients A vehicle-controlled clinical trial

Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al Arch Dermatol 1994;

130:727–733

This study compared the treatment of melasma with

ada-palene 0.1% vs 0.05% tretinoin A total of 30 subjects

from India were randomized in a 14-week trial where they

were assigned to either group Results showed that subjects in

the adapalene group had a 41% reduction in melasma

treat-ment area and severity index versus 37% in the tretinoin

group The difference between the two groups was not

statisti-cally significant Adverse events were significantly higher for

tretinoin patients, 63% vs 22% in the adapalene treated

subjects

Second-Line Therapies

Double-blind comparison of azelaic acid and hydroquinone

in the treatment of melasma Verallo-Rowell VM, Verallo V,

Graupe K, Lopez-Villafuerte L, Garcia-Lopez M Acta Derm

Venereol Suppl (Stockh) 1989; 143:58–61

The goal of this randomized, double-blind study was to

evaluate the clinical efficacy of azelaic acid (20%) and

hydro-quinone creams (2%) in the treatment of melasma 155

patients of Indo-Malay-Hispanic origin were assigned to either

treatment group and instructed to apply study medication

twice daily A broad spectrum sunscreen was used

concomi-tantly Over a period of 24 weeks, 73% of the azelaic acid

patients, compared with 19% of the hydroquinone patients,

had good to excellent overall results, as measured by the

reduction of melasma pigmentary intensity and lesion size

Transient mild to moderate irritant reactions were initially

seen with both test drugs

The treatment of melasma 20% azelaic acid versus 4%

hydroquinone cream Baliña LM, Graupe K Int J Dermatol

1991; 30(12):893–895

This 24-week, double-blind study evaluated the efficacy of

20% azelaic acid cream and 4% hydroquinone cream, both

used in conjunction with a broad spectrum sunscreen for

melasma 329 women were enrolled and assigned to either

treatment group Over the treatment period, azelaic acid cream

yielded 65% with good or excellent results; however, no

sig-nificant treatment differences were observed with regard to

overall rating, reduction in lesion size, and pigmentary

inten-sity Severe side effects such as allergic sensitization or

exoge-nous ochronosis were not observed with azelaic acid

Topical azelaic acid in the treatment of melasma:

pharma-cological and clinical considerations In: Graupe K, Balina

LM Melasma – new approaches to therapy London:

Martin-Dunitz; 1995:19–41

50 subjects with melasma were enrolled in this open-label,

randomized study for 24 weeks Subjects were assigned to

receive either 20% azelaic acid or 20% azelaic acid with

tretinoin 0.05% Results demonstrated the combination

group as having excellent results (34.8%) vs 5.3% of the

azelaic acid group with excellent results

Lim J, Eun H, Park K Dermatology 2003; 206:316–320.

29 females with melasma were enrolled in this blind, placebo-controlled trial The purpose of this study was

double-to evaluate the efficacy of vitamin C iondouble-tophoresis for melasma patients For iontophoresis, a vitamin C solution was applied

to one side of the face, while distilled water was applied to the other side as a control The L (luminance) value was measured

by a colorimeter to obtain an objective pigmentation meter 12 weeks after iontophoresis, the colorimeter of the treated site showed a significant decrease in the L value (from 4.60 to 2.78, p = 0.002), compared to that of the control site (from 4.45 to 3.87, p = 0.142) The results showed that vitamin

para-C iontophoresis may be an effective treatment modality for melasma

Experience with a strong bleaching treatment for skin hyperpigmentation in Orientals Yoshimura K, Harii K,

Aoyama T, Iga T Plast Reconstr Surg 2000; 105(3):1097–1108;

discussion 1109–10

In this study, 136 Oriental patients were analyzed and lowed for more than 12 weeks The treatment protocol was composed of two steps: bleaching (2–6 weeks) and healing

fol-(2–6 weeks); 0.1–0.4% all-trans retinoic acid aqueous gel

was originally prepared and applied concomitantly with hydroquinone-lactic acid ointment for bleaching After obtain-ing sufficient improvement of the hyperpigmentation, a corticosteroid was applied topically with hydroquinone and ascorbic acid for healing Improvement was evaluated with a narrow-band reflectance spectrophotometer The results were successful in more than 80% of cases of senile lentigines and post-inflammatory hyperpigmentation, especially on the face 60% of cases of nevus spilus were also successfully treated Although the transient adverse effects of this treatment may be more severe than conventional treatment, this strong bleach-ing protocol improves a variety of hyperpigmented lesions, including nevus spilus, with a higher success rate and a shorter treatment period than conventional protocols

Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma Yamakoshi J, Sano A, Tokutake S,

et al Phytother Res 2004; 18(11):895–899

This study investigated the reducing effect of nidin, a powerful antioxidant, on chloasma in a one-year open design study 12 Japanese women received proanthocyanidin-rich grape seed extract (GSE) orally The treatment was admin-istered to candidates with chloasma for 6 months between

proanthocya-10 Hyperpigmented Disorders • Mongolian spots

studied to be considered safe during pregnancy or during lactation

Although lasers have been used to treat melasma, the majority of studies show that lasers may exacerbate the condition, minimally improve it, or produce unwanted post-inflammatory hyperpigmentation The physician should use caution when considering laser treatment and select lasers appropriate for the patient’s skin type

Discontinuation of oral contraceptives is recommended as

an adjunct to treatment but it is imperative that another method of contraception be suggested as an alternative.Special management & counseling considerationsThe psychosocial impact of melasma on the patient is an aspect of the disease that requires close attention by clinicians Emotional support and reassurance are key The patient must understand that while treatment is available, improvement may be incomplete and slow

Management of melasma also includes the use of flaging cosmetics and sun protection in the form of sunscreen and protective clothing The use of broad-spectrum sunscreens

camou-of at least SPF 30, applied daily and re-applied every 2 hours

is critically important for the treatment of melasma screens should be used on a daily basis Abrasive cleansers should also be avoided

Sun-References

1 Ortonne JP, Bissett DL Latest insights into skin hyperpigmentation

J Invest Dermatol Symp Proc 2008; 13:10–14.

2 Draelos ZD Melasma: introduction and disease background In: Flucinolone acetonide, hydroquinone and tretinoin: unique and effective combination treatment for melasma Virtual Symposium CD-ROM, 2001.

3 Rendon MI Utilizing combination therapy to optimize melasma comes J Drugs Dermatol 2004; 3(5 Suppl):S27–S34.

out-4 Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC Melasma: a clinical, light microscopic, ultrastructural, and immun- ofluorescence study J Am Acad Dermatol 1981; 4:698–710.

5 Grimes PE Melasma Etiologic and therapeutic considerations Arch Dermatol 1995; 131:1453–1457.

6 New Zealand Dermatological Society Melasma http://dermnetnz.org/ colour/melasma.html [accessed September 22, 2009].

August 2001 and January 2002 and to 11 of these 12 for 5

months between March and July 2002 Clinical observation,

L* value (luminance) and melanin index, and size (length and

width) measurements of chloasma were performed

through-out the study period The first 6 months of GSE intake improved

or slightly improved chloasma in 10 of the 12 women (83%,

p < 0.01) and the following 5 months of intake improved or

slightly improved chloasma in 6 of the 11 candidates (54%, p

< 0.01) L* values also increased after GSE intake (57.8 ± 2.5

at the start vs 59.3 ± 2.3 at 6 months and 58.7 ± 2.5 at the end

of study) Melanin index significantly decreased after 6 months

of the intake (0.025 ± 0.005 at the start vs 0.019 ± 0.004 at 6

months; p < 0.01), and also decreased at the end of the study

(0.021 ± 0.005; p < 0.05) GSE is effective in reducing the

hyperpigmentation of women with chloasma The beneficial

effects of GSE were maximally achieved after 6 months and

there was no further improvement after this period The latter

GSE intake for 5 months may prevent chloasma from

becom-ing worse prior to the summer season GSE is safe and useful

for improving chloasma

followed by Q-switched alexandrite laser: a pilot study

Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J Dermatol

Surg 1999; 25(6):494–497

The objective of this study was to compare pulsed CO2 laser

alone with the combination of pulsed CO2 laser followed by

Q-switched alexandrite laser in the treatment of dermal-type

melasma 4 patients were randomly chosen for each treatment

arm This combination is proposed to be effective by first

destroying the abnormal melanocytes with the pulsed CO2

laser and then selectively eliminating the dermal melanin with

the alexandrite laser Patients received multiple follow-up

visits for examination by an objective blinded investigator All

patients in the combination laser group showed complete

resolution, and 2 patients in the CO2 laser only group had

peripheral hyperpigmentation in the long-term follow-up

evaluation The results showed that these laser therapies are

safe from scarring and infection The combination laser

therapy was highly effective in removing the

hyperpigmenta-tion and all patients in this group showed complete resoluhyperpigmenta-tion

without any peripheral hyperpigmentation

Commonly encountered pitfalls

Pregnancy is commonly associated with melasma Agents used

to treat melasma may be either teratogenic or insufficiently

lesions are almost always blue or gray in color The diameter

of the lesions is usually several centimetres in diameter One macule or patch may be present, however, some patients may have numerous lesions Abnormal melanocyte migration has been theorized as one cause of MS

Mongolian spots are usually present at birth or appear within the first weeks of life.1 Several ethnic groups are

Mongolian spots

Mongolian spots (MS), a type of dermal melanocytosis

involves the lumbosacral area of healthy infants (Fig 10.10).1,2

The buttocks, flanks, and shoulders may be affected The

Figure 10 10: Mongolian spot (From Johnson, Moy, White: Ethnic Skin – Medical

and Surgical, Mosby Inc , copyright Elsevier 1998 )

particularly prone to MS, with Asians as the highest among

them It is observed in more than 90% of Asian infants Laude

reports that over 95% of African-American babies have

Mon-golian spots (Table 10.4)

In a study of Nigerian children, 369 neonates and 484

children aged 1 month to 14 years were evaluated for the

pres-ence of MS MS were present in over 381 children with an

overall incidence of 44.7% (74.8% of neonates and 13.6% of

pre-school children) There was no sexual predilection Traces

of MS disappeared with advanced age and no MS were found

in children over 6 years old.2 However, in some instances MS

can persist for life (Fig 10.11).3

Although MS are typically benign blue-gray discolorations,

extensive Mongolian spots can indicate possible inborn errors

of metabolism There was a report of three infants with

exten-sive MS of whom two had GM1 gangliosidosis type 1, and a

third had an associated Hurler Syndrome It is therefore

important to diagnose extensive MS so that early treatment

may be possible.4

In another observational report from Northern Italy, 620

healthy neonates were examined to study birthmarks and

tran-sient cutaneous lesions in newborns of different ethnic groups

Hyperpigmentation in the genital area and MS were positively

associated with geographical area of origin and were more

common in non-European neonates There was a positive

cor-relation between melanocytic congenital nevi in Asian

new-borns as well as a salmon patch on the nape of women who

were greater than 35 years of age.5

Since MS are benign lesions which may rapidly disappear,

treatment is not necessary However, if lesions of MS are

exten-sive, the physician should examine the neonate for a possible

genodermatosis

First-Line Therapies

Q-switched Ruby laser and Q-switched Nd-YAG laser D

Laser treatment of 26 Japanese patients with Mongolian spots Kagami S, Asahina A, Watanabe R et al Dermatol Surg

2008; 34(12):1689–1694

26 patient study in which the Q-switched alexandrite laser was used to treat MS with a good outcome Of interest, the authors found that better outcomes were achieved when treat-ments were started at a younger age Therefore, a recommenda-tion was made to begin treatment for sacral and extra-sacral

MS before the age of 20

Aberrant Mongolian spot Kobayashi M, Kubota J, Ogo K

Japanese J Plast Reconstr Surg 2001; 44:1193–1196

The Q-switched Ruby laser and Q-switched Nd-YAG laser were successful for treatment of aberrant Mongolian spots (lesions that persist past the age of 5 or 6) As in the above study, treatment at a younger age is preferred

Table 10 4 Prevalence of skin manifestations*

Skin manifestation

School-aged children

Pre-school-aged children

Dermatitis and/or eczema related

Xerosis 536 (37 8) 118 (8 3)Dennie Morgan fold 143 (10 1) 48 (3 4)Keratosis pilaris 220 (15 5) 53 (3 7)Atopic dermatitis 73 (5 1) 32 (2 3)Pityriasis alba† 12 (0 8) 6 (0 4)

Disorders of pigmentation

Acquired melanocytic nevi 558 (39 4) 202 (14 3)Mongolian spot‡ 0 103 (7 3)Café au lait macules‡ 93 (6 6) 58 (4 1)Congenital melanocytic nevi 47 (3 3) 39 (2 8)

343 (24 2) 0Vascular lesions 37 (2 6) 58 (4 1)Hair disorders 46 (3 3) 3 (0 2)Nail disorders 26 (1 8) 7 (0 5)

*Data are reported as number (percentage) of affected children.

†Male predominance (p < 02).

‡There is a significant correlation between coexistence of Mongolian spots and café au lait macules (p < 001).

10 Hyperpigmented Disorders • Nevus of Ota

Special management & counseling considerations

Mongolian spots have been confused with ecchymotic lesions

resulting from child abuse Parents of children with

Mongo-lian spots have been falsely accused of child abuse In these

cases, the specialist must educate and provide clarification

about the differences between these lesions.6 Additionally, it

Figure 10 11: The Mongolian spot is found on the sacrum or low back at birth

and tends to fade, often disappearing completely within a few years (From White &

Cox, Diseases of the Skin, A Color Atlas and Text, 2E, Mosby Inc, copyright Elsevier

Commonly encountered pitfallsMongolian spots have been found in children with a multi-tude of various diseases Extensive, aberrant Mongolian spots

in children with mucopolysaccharidosis and GM1 sidosis have been reported and should merit evaluation by a specialist well versed in inborn errors of metabolism

ganglio-References

1 Kibbi AG, Bahhady RF, Tannous Z, et al Mongolian spot http:// emedicine.medscape.com/article/1068732-overview [accessed Septem- ber 15, 2009].

2 Onayemi O, Adejuyigbe EA, Torimiro SE, et al Prevalence of golian spots in Nigerian children in Ile-Ife, Nigeria Niger J Med 2001; 10(3):121–123.

Mon-3 Cordova A The Mongolian spot: a study of ethnic differences and a literature review Clin Pediatr (Phila) 1981; 20(11):714–719.

4 Rybojad M, Moraillon I, Ogier de Baulny H, et al Extensive Mongolian spot related to Hurler disease Ann Dermatol Venereol 1999; 126(1):35–37.

5 Boccardi D, Menni S, Ferraroni M, et al Birthmarks and transient skin lesions in newborns and their relationship to maternal factors: a pre- liminary report from northern Italy Dermatology 2007; 215(1): 53–58.

6 Laude TA Approach to dermatologic disorders in black children Semin Dermatol 1995; 14(1):15–20.

Cosmetic makeup can minimize the disfiguring facial mentation resulting from Nevus of Ota Otherwise, topical therapy is of no value in medical treatment Some surgical procedures have shown results in treating Nevus of Ota

pig-Nevus of Ota

The etiology of Nevus of Ota is unknown It commonly occurs

on the face, namely the periocular skin and sclera, and

repre-sents dermal melanocytes in the epidermis.1 It is described

as a speckled, bluish-brownish and even grayish facial

patch Of interest, its distribution has been known to follow

that of the first and second branches of the trigeminal nerve2

(Figs 10.12, 10.13)

Pigmentation can be unilateral or bilateral and can also

involve the buccal mucosa.3 Histologically it is

indistinguish-able from a Nevus of Ito, except that the latter are found on

the shoulder and upper arms as opposed to the face.4 Its onset

occurs in the early years of life and lesions can multiply in

number and converge.5 The incidence of this condition is

common in Asian populations, with an estimated prevalence

in Japanese society of 0.2–1%.6

Disturbingly Nevi of Ota have been associated with

deaf-ness.7 Of even more concern, malignant transformations have

been reported.8,9

Pulsed Q-switched laser surgery is unquestionably the current treatment of choice for Nevi of Ota and Ito It works via selective photothermal and photomechanical destruction

of dermal melanocytes and melanophages High success rates and minimal adverse effects have been reported with the Q-switched ruby,3 Q-switched alexandrite,1,2 and Q-switched Nd:YAG lasers.1 After 4–8 treatments, skin pigmentation is reduced dramatically or removed in 90–100% of cases, with

< 1% risk of scarring

First-Line Therapies

Q-switched ruby laser 10,11,12,13 C

Figure 10 12: Nevus of Ota in a black skinned child (From Johnson, Moy, White:

Ethnic Skin – Medical and Surgical, Mosby Inc , copyright Elsevier 1998 )

Figure 10 13: Nevus of Ota-like macules This condition is common in East-Asian

women and may be confused with sun damage (From White & Cox, Diseases of

the Skin, A Color Atlas and Text, 2E, Mosby Inc , copyright Elsevier 2006 )

Nevus of Ota: treatment with high energy fluences of the

Q-switched ruby laser Lowe NJ, Wieder JM, Sawcer D, et al

J Am Acad Dermatol 1993; 29(6):997–1001

A 16 patient study in which a Q-switched ruby laser was

used to treat Nevi of Ota After two treatments, 44% of patients

showed > 50% improvement With three treatments, 85% of

patients showed > 50% improvement After four treatments,

100% of the patients showed > 50% improvement No

seque-lae from the laser were noted

Other surgical methods have been superseded by laser

surgery They include:

• cryotherapy4

• microsurgery

• dermabrasion (alone or combined with other modalities, such as carbon dioxide snow, autologous epithelial grafting)

• sequential dry ice epidermal peeling

Commonly encountered pitfallsMalignant degeneration of Nevi of Ito and Ota have been reported and the clinician should be mindful of changes that are suggestive of melanoma Furthermore, Nevi of Ota with ocular involvement present an increased risk of choroidal melanoma and glaucoma Regular ophthalmic examinations should be recommended

Special management & counseling considerationsNevi of Ota/Ita present cosmetic concerns to parents during early childhood and to the patient from adolescence through adulthood Therefore, it is important to carefully discuss avail-able cosmetics and surgical treatments

References

1 Mishima Y Melanocytic tumors In: Zelickson AS, ed Ultrastructure

of normal and abnormal skin Philadelphia: Lea & Febiger; 1967: 388–424.

2 Carleton A, Biggs R Diffuse mesodermal pigmentation with tal cranial abnormality Br J Dermatol Syphilol 1948; 60:10–33.

congeni-3 Dermnet NZ Naevi of Ota and Ito http://www.dermnet.org.nz/ lesions/naevus-ota-ito.html [Accessed December 19, 2009].

4 Lui H, Zhou Y Nevi of Ota and Ito Emedicine http://emedicine medscape.com/article/1058580-overview [Accessed December 19, 2009].

5 Fitzpatrick TB, Zeller R, Kukita A, et al Ocular and dermal tosis AMA Arch Ophthalmol 1956; 56:830–832.

melanocy-6 Turnbull JR, Assaf Ch, Zouboulis C, Tebbe B Bilateral naevus of Ota:

a rare manifestation in a Caucasian J Eur Acad Dermatol Venereol 2004; 18(3):353–355.

7 Alvarez-Cuesta CC, Raya-Aguado C, Vázquez-López F, et al Nevus

of Ota associated with ipsilateral deafness J Am Acad Dermatol 2002; 47(5 Suppl):S257–S259.

8 Patterson CR, Acland K, Khooshabeh R Cutaneous malignant melanoma arising in an acquired naevus of Ota Australas J Dermatol 2009; 50(4):294–296.

9 Dorsey CS, Montgomery H Blue Nevus and its distinction from Mongolian Spot and the naevus of ota J Invest Dermatol 1954; 22:225–236.

10 Watanabe S, Takahashi H Treatment of nevus of Ota with the Q-switched ruby laser N Engl J Med 1994; 331(26):1745–1750

11 Chan HH, Leung RS, Ying SY, et al A retrospective analysis of cations in the treatment of nevus of Ota with the Q-switched alexan- drite and Q-switched Nd:YAG lasers Dermatol Surg 2000; 26(11): 1000–1006

compli-12 Wang HW, Liu YH, Zhang GK, et al Analysis of 602 Chinese cases of nevus of Ota and the treatment results treated by Q-switched alexan- drite laser Dermatol Surg 2007; 33(4):455–460

13 Chan HH, Leung RS, Ying SY, et al A retrospective analysis of cations in the treatment of nevus of Ota with the Q-switched alexan- drite and Q-switched Nd:YAG lasers Dermatol Surg 2000; 26(11): 1000–1006

compli-10 Hyperpigmented Disorders • Pigmentary demarcation lines

Pigmentary

demarcation lines

Pigmentary demarcation lines (PDL), also known as Futcher’s

lines or Voight’s lines were first described by the Viennese

anatomist Christian A Voight Although there is no known

etiology, this condition is associated with pregnancy.1

Interest-ingly, there is a recent case of a 51-year-old amenorrheic

Chinese woman who developed PDL which were attributed to

a hormonal imbalance

PDL are more common in African and Japanese

popula-tions There is no evidence that supports an age or sex

predilec-tion The lines are classified into six different types based on

anatomical location: type A, B, C, D, E, and F.2

• Type A – lines run along the upper limb with variable

trans-pectoral extensions They are commonly observed

in Japanese women as well as in Hispanics and Blacks

(Fig 10.14)

• Type B – lines run along the lower limbs They have

been observed in Japanese women and are accentuated

during pregnancy in Hispanic women with post-partum

resolution

• Type C – lines present as paired median or paramedian

lines on the chest with midline abdominal extension They

have been reported in African-American and Japanese

women

• Type D – lines present on the posteromedial area of the

spine can mimic tinea versicolor, vitiligo and

post-inflammatory hypopigmentation

• Type E – Hypopigmented macules located on the chest

extending from the clavicle to the periareolar skin; typically

bilaterally symmetrical

• Type F – Lines on the face.

Figure 10 14: Type A pigmentary demarcation lines (From Johnson, Moy, White:

Ethnic Skin – Medical and Surgical, Mosby Inc , copyright Elsevier 1998 )

A

B

First-Line Therapy

Q-switched alexandrite laser E

Treatment of PDL may be considered a cosmetic problem

However, patients have been treated with the Q-switched

alex-andrite laser

Effective treatment of Futcher’s lines with Q-switched

alex-andrite laser Bukhari IA J Cosmet Dermatol 2005; 4(1):

27–28

Case report of a young female patient who presented with

type A pigmentary demarcation lines on the anterolateral

aspect of both arms, which were satisfactorily treated with a

Q-switched alexandrite laser with no adverse effects

Commonly encountered pitfallsThe development of pigmentary demarcation lines in a female may signal pregnancy Cases of hormonal imbalances in non-pregnant women with sudden onset of pigmentary demarca-tion lines are of interest but do not infer any medical problem

1 James WD, Meltzer MS, Guill MA, Berger TG, Rodman OG Pigmentary demarcation lines associated with pregnancy J Am Acad Dermatol 1984; 11:438–440.

2 Selmanowitz VJ, Krivo JM Pigmentary demarcation lines Comparison

of Negroes with Japanese Br J Dermatol 1975; 93:371–377.

Figure 10 15: Post-inflammatory hyperpigmentation from arthropod bites

Special management & counseling considerations

Commonly found in individuals with ethnic skin, these

benign findings should be of little concern to patients

Camouflage with cosmetics and laser therapy can be offered

as treatment Pregnant women whose development of PDL is

attributed to pregnancy can expect resolution after delivery

Table 10 5 Causes of post-inflammatory hyperpigmentation

• Cutaneous T-cell lymphoma

Figure 10 16: Post-inflammatory hyperpigmentation from tinea corporis

Figure 10 17: Post-inflammatory hyper- and hypo-pigmentation secondary to a

laser burn

Post-inflammatory

hyperpigmentation (PIH)

Post-inflammatory hyperpigmentation (PIH) is a very common

disorder in black, Hispanics and Asian patients.1 It can occur

as sequela of virtually any inflammatory condition (Table 10.5,

Figs 10.15–10.17) Papulosquamous and vesiculobullous

dis-eases are also commonly associated conditions.1 The etiology

of PIH is unknown However, the specific release of

inflamma-tory mediators and cytokines from inflammainflamma-tory cells as well

as keratinocytes may play an active part in the pathogenesis of the condition.1 Cytokines and inflammatory mediators that stimulate melanocytes2 and melanogenesis include: endothe-lins, prostaglandin D2 and E2, interleukin 1 and 6, and tumor necrosis factor alpha.3 A decrease in melanogenesis has been reported to be caused by C4 Movement of melanocytes can be caused by leukotriene, C4, and transforming growth factor alpha.2 Mediators may be specific for each skin condi-tion and responsible for either increased melanogenesis or

10 Hyperpigmented Disorders • Post-inflammatory hyperpigmentation (PIH)

severity, pigmentation intensity, lesion area, and colorimetry assessments were evaluated A broad-spectrum sunscreen was applied once in the morning, 15 minutes after application of the test product Patients were evaluated at baseline and at 4,

8, and 12 weeks HQ 4% and retinol 0.15% formulation duced improvement at all study endpoints Improvement in disease severity and pigmentation intensity was statistically significant at weeks 4, 8, and 12 compared with baseline (p < 0.001) Lesion area and colorimetry measurements also were significantly improved at each visit (p < 0.001) The treatment was deemed safe and effective

pro-decreased melanogenesis, leading to hyperpigmentation or

hypopigmentation

The goal of therapy is treatment of the underlying disease

and prevention of PIH It must be said that many of the

treat-ments that are effective for PIH are also effective for melasma,

thus consulting the section on melasma earlier in this chapter

Hydroquinone 4% and retinol 0 15% C

The effectiveness & safety of Lustra (hydroquinone USP

4%) in dyschromia Rizer R, Sklar J, Hino P, et al Skin &

Aging 1999; (Suppl 1):4–8

Single-blind, randomized, controlled, 12-week study

com-paring the efficacy and tolerance of hydroquinone 4% vs

hydroquinone 3% vs hydroquinone cream 4% with sunscreens

SPF 17 The study included 69 female subjects (35–55 years

old) with relatively equal numbers of Caucasian, Asian, and

African-American individuals Hydroquinone 4% had a faster

onset of activity and a greater decrease in pigmentation when

compared to the two other treatment arms In addition, Lustra

showed improvement in fine lines, smoothness, and clarity

compared to the other agents

Study of hydroquinone USP 4%, 0.05% tretinoin, and in

combination in UV-induced dyschromia with actinic

photo-damage Swinyer LJ, Wortzman M Cosmetic Dermatol 2000;

13:13–18

Investigator-blind, randomized, controlled study

compar-ing the efficacy and safety of hydroquinone cream 4% cream

vs tretinoin emollient cream 0.05% vs hydroquinone cream

4% cream plus tretinoin emollient cream 0.05% 42 subjects

with moderate-to-severe facial dyschromia and actinic

photo-damage were evaluated for 12 weeks The cream was applied

twice daily and subjects were also provided with a sunscreen

(SPF 25) and a moisturizer Investigators assessed blotchiness,

mottled hyperpigmentation, PIH, and surface roughness The

group using hydroquinone cream 4% alone and the group

using tretinoin emollient cream 0.05% plus hydroquinone

cream 4% cream produced a more rapid and greater reduction

in mottled hyperpigmentation compared to tretinoin

emol-lient cream 0.05% alone

A microsponge formulation of hydroquinone 4% and

retinol 0.15% in the treatment of melasma and

post-inflammatory hyperpigmentation Grimes PE Cutis 2004;

74(6):362–368

25 patient open-label study of hydroquinone 4% and

retinol 0.15% applied twice daily for 12 weeks Disease

hyperpig-Grimes P, et al Clin Ther 1998; 20(5):945–959

Multicenter, randomized, double-masked, parallel-group study assessing the efficacy, safety, and tolerability of azelaic acid 20% cream compared to vehicle for the treatment of facial hyperpigmentation in darker-skinned patients, Fitzpatrick skin types IV–VI Subjects were treated for 24 weeks Azelaic acid produced significantly greater decreases in pigmentary inten-sity than did vehicle as measured by both investigator’s subjec-tive scale (p = 0.021) and chromometer analysis (p = 0.039) There was significantly greater overall improvement with azelaic acid than with placebo at week 24 (p = 0.008) Adverse events experienced with the treatment arm included burning and stinging

Melanin hyperpigmentation of skin: melasma, topical ment with azelaic acid, and other therapies Breathnach AS

treat-Cutis 1996; 57(1 Suppl):36–45

Topical 20% azelaic acid is superior to 2% hydroquinone and as effective as 4% hydroquinone in the treatment of post-inflammatory hyperpigmentation The effect of azelaic acid can be attributed to its ability to inhibit the energy production and/or DNA synthesis of hyperactive melanocytes, and par-tially to its anti-tyrosinase activity

The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions

Garcia A, Fulton JE Dermatol Surg 1996; 22(5):443–447

39 patients were treated with kojic acid on one side of the face and hydroquinone in a similar vehicle on the other side

of the face 51% of the patients responded equally to quinone and kojic acid 28% had a more dramatic reduction

hydro-in pigment on the kojic acid side; whereas 21% had a more dramatic improvement with the hydroquinone formulation These results were not statistically different The kojic acid preparation was more irritating

Commonly encountered pitfallsPatients must be cautioned about the protracted nature of post-inflammatory hyperpigmentation which may take months or years to resolve Treatments may be partially effec-tive or in the case of dermal pigmentation, ineffective.For patients with darker skin tones, a variety of surgical, cosmetic or laser treatments may lead to post-inflammatory hyperpigmentation (Fig 10.17) It is important to inform the patient prior to any of these procedures of this possible consequence.

Treatment of post-inflammatory hyperpigmentation with products containing hydroquinone as the active ingredient may result in a ‘halo’ of hypopigmentation surrounding the treatment area (Fig 10.18) The patient should be reas-sured that this halo will resolve spontaneously once the hydroquinone-containing product is discontinued

Special management & counseling considerationsSun protection and daily use of SPF 30 or higher sunscreens are essential management strategies Broad-spectrum sun-screens must be used and re-applied every 2 hours Patients must be counseled on discontinuation of any offending agent

Patients should be warned about the use of containing products for the treatment of post-inflammatory hyperpigmentation These agents are often obtained from beauty supply stores in major metropolitan areas They have been illegally imported into the United States

corticosteroid-Treatment of melasma using kojic acid in a gel containing

hydroquinone and glycolic acid Teng Ee Lim J Dermatol

Surg 1999; 25:282–284

40 women with epidermal melasma were treated with 2%

kojic acid in a gel containing 10% glycolic acid and 2%

hyd-roquinone on one half of the face The other half was treated

with the same application but without kojic acid At 12 weeks,

more than half of the melasma cleared in 24/40 (60%) patients

receiving kojic acid compared to 19/40 (47.5%) patients

receiving the gel without kojic acid Again, redness, stinging,

and exfoliation were observed side effects

Many of the treatments that are effective for PIH are also

effec-tive for melasma and vice versa.

Glycolic acid peels for post-inflammatory

hyperpigmenta-tion in Black patients A comparative study Burns RL,

Prevost-Blank PL, Lawry MA Dermatol Surg 1997;

23(3):171–175

19 patients with Fitzpatrick skin type IV, V, or VI were

ran-domized to a control or peel group The control group applied

2% hydroquinone/10% glycolic acid gel twice daily and 0.05%

tretinoin cream at night The peel patients used the same

topical regimen and, in addition, received six serial glycolic

acid peels (68% maximum concentration) The patients

receiv-ing the glycolic acid peels showed a trend toward more rapid

and greater improvement The peel group also experienced

increased lightening of the normal skin

The safety and efficacy of salicylic acid chemical peels in

darker racial-ethnic groups Grimes PE Dermatol Surg 1999;

25(1):18–22

25 patients with skin types V and VI, with various

inflam-matory cutaneous disorders (including 5 with PIH) were

pre-treated for 2 weeks with hydroquinone 4% prior to undergoing

a series of five salicylic acid chemical peels The concentrations

of the salicylic acid peels were 20% and 30% The peels were

performed at 2-week intervals Moderate to significant

improve-ment was observed in 88% of the patients Minimal to mild

side effects occurred in 16%

Third-Line Therapies

Ineffective treatment of refractory melasma and

postinflam-matory hyperpigmentation by Q-switched ruby laser Taylor

CR, Anderson RR J Dermatol Surg Oncol 1994; 20(9):

592–597

8 subjects with melasma or post-inflammatory

hyperpig-mentation refractory to traditional treatments were treated

with Q-switched ruby laser pulses No permanent

improve-ment and, in some cases, darkening was seen in each type of

lesion Several months later, epidermal pigmentation had

returned to baseline This is an ineffective and sometimes

counterproductive treatment

Figure 10 18: Halo of hypopigmentation from hydroquinone treatment

10 Hyperpigmented Disorders • Solar lentigines

References

1 Halder RM, Nootheti PK Ethnic skin disorders overview J Am Acad

Dermatol 2003; 48(6 Suppl):S143–S148.

2 Morelli JG, Norris DA Influence of inflammatory mediators and

cytokines on human melanocyte function J Invest Dermatol 1993;

100(2 Suppl):191S–195S.

Figure 10 19: Solar lentigines

Solar lentigines

Solar lentigines are usually well demarcated brown macules

which result from an increased number of melanocytes in the

epidermis.1 They may vary in color from light brown to black

and vary in size from a millimeter to a few centimeters.2 Solar

lentigines can coalesce and are found in sun exposed areas,

e.g hands, arms, shoulder and face (Figs 10.19, 10.20) They

usually begin after the 4th decade of life and may occur after

acute or chronic sun exposure

There are certain diseases which may be associated with

Table 10 6 Characteristics of Solar Lentigines

Brown to black macules ranging in size from 1 mm to several centimeters

Increase in melanin production, possible increased number of melanocytes

Occurs only in the epidermisInduced by UV lightMore common in skin types I–III

3 Morelli JG, Kincannon J, Yohn JJ, et al Leukotriene C4 and TGF-alpha are stimulators of human melanocyte migration in vitro J Invest Dermatol 1992; 98(3):290–295.

Figure 10 20: Solar lentigines on the upper back

Solar lentigines may show a linear increase in the cytes at the dermato-epidermal junction.4 Characteristics of solar lentigines are found in Table 10.6

melano-First-Line Therapies

PhotoprotectionBroad spectrum sunscreenProtective clothing and hats

The combination of 2% 4-hydroxyanisole (mequinol) and

0.01% tretinoin is effective in improving the appearance of

solar lentigines and related hyperpigmented lesions in two

double-blind multicenter clinical studies Fleischer AB Jr,

Schwartzel EH, Colby SI et al J Am Acad Dermatol 2000;

42:459–467

This study evaluated subjects that were either randomized

to treatment with topical 2% 4-HA / 0.01% tretinoin solution,

2% 4-HA or 0.01% tretinoin or vehicle (placebo) The 4-HA/

tretinoin combination was found to be superior to either of

the active components alone or placebo

Topical tretinoin (retinoic acid) treatment for liver spots

associated with photodamage Rafal ES, Griffiths CE, Ditre

CM, et al N Engl J Med 1992; 326(6):368–374

A 10-month randomized double-blind study of 58 patients

who applied either 0.1% tretinoin (28) or placebo cream daily

to the face, upper extremities, or both After 1 month of

treat-ment, the patients treated with tretinoin had improvement of

hyperpigmented lesions as compared with the patients who

received placebo After 10 months, 20 (83%) of the 24 patients

with facial lesions who were treated with tretinoin had

lighten-ing of these lesions, as compared with 8 (29%) of the 28

patients with facial lesions who received placebo The results

for lesions of the upper extremities were similar

Analytic quantification of solar lentigines lightening by a

2% hydroquinone-cyclodextrin formulation Petit L, Piérard

GE J Eur Acad Dermatol Venereol 2003; 17:546–549

30 Asian adults applied a 2% hydroquinone-cyclodextrin

formulation (used as a novel delivery vehicle) once daily on

solar lentigines of one forearm, for 2 months; the other

forearm served as the control The areas treated with 2%

hydroquinone showed improvement when compared to the

control area

Experience with a strong bleaching treatment for skin

hyperpigmentation in Orientals Yoshimura K, Harii K,

Aoyama T, et al Plast Reconstr Surg 2000; 105:1097–1108;

discussion 1109–1110

136 Asians were treated with a 0.1–0.4% all-trans retinoic

acid aqueous gel and hydroquinone-lactic acid ointment

More than 80% of cases of solar lentigines improved though

a topical steroid had to be applied with hydroquinone and

Vitamin C to induce healing

Second-Line Therapies

Chemical peels: trichloroacetic acid peels B

trichloroacetic acid peel Complete regression of localized hyperpigmentations was observed in 8 of 20 patients (40%),

a partial regression in 10 of 20 patients (50%), and no sion in 2 of 20 patients (10%) treated with 15–25% trichloro-acetic acid

IPL (Intense Pulsed Light) B

Cryosurgery has been used for many decades with selective destruction of melanocytes However, cryosurgical destruction

may lead to hypopigmentation therefore treatment must be

Q-switched ruby laser application is safe and effective for the management of actinic lentigo (topical glycolic acid is not) Kopera D, Hohenleutner U, Landthaler A, et al Derm

Venereol 1996; 76:461–463

10 female patients with actinic lentigines on the forearms and dorsal aspects of their hands were treated with the Q-switched ruby laser on the right side A glycolic acid peel was performed on the left side 4 weeks after treatment with the laser, total fading of the lesions was evident However, the glycolic acid peel did not clear the lesions and caused signifi-cant adverse events such as burning, irritation and scaling

The use of the frequency-doubled Q-switched Nd:YAG laser in the treatment of small cutaneous vascular lesions

Goldberg DJ, Marcus J Dermatol Surg 2008; 22:841–844.Three-center trial examining the performance of the Nd: YAG laser on 49 patients with benign pigmented lesions Cuta-neous lesions showed improvement with use of the laser, espe-cially at the higher intensity setting

Laser therapy versus cryotherapy of lentigines: a tive trial Stern RS, Dover JS, Levin JA, et al J Am Acad Der-

compara-matol 1994; 30:985–987

The use of chemical peelings in the treatment of different

cutaneous hyperpigmentations Cotellessa C, Peris K, Onorati

MT, et al Dermatol Surg 1999; 25:450–454

20 patients with diffuse melasma were treated with a

solution composed of 50% glycolic acid and 10% kojic acid

peel, and 20 patients with lentigo were treated with 15–25%

10 Hyperpigmented Disorders • Pediatric perspectives: Transient neonatal pustular melanosis

improvement Patients with smaller lesions responded better

to this treatment modality than those with larger lesions.References

1 Ortonne JP, Bahadoran P, Fitzpatrick TB, et al Hypomelanoses and hypermelanoses In: Freedberg IM, et al, eds Fitzpatrick’s dermatology

in general medicine 6th edn New York: McGraw-Hill; 2003:836– 881.

2 Hexsel DM, Mazzuco R, Bohn J, et al Clinical comparative study between cryotherapy and local dermabrasion for the treatment of solar lentigo on the back of the hands Dermatol Surg 2000; 26:457–462.

3 Cayce KA, McMichael AJ, Feldman SR Hyperpigmentation: an view of the common afflictions Medscape Today [accessed August 27, 2009].

over-4 Bose S, Ortonne JP Pigmentation: dyschromia Cosmet Dermatol 1994; 277–298.

5 Rafal ES, Griffiths CE, Ditre CM, et al Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage N Engl J Med 1992; 326(6):368–374.

Randomized, controlled, prospective trial comparing liquid

nitrogen cryotherapy, argon laser and a carbon dioxide laser

irradiation in the treatment of solar lentigines at 99 sites in 13

patients Researchers found that cryotherapy was more likely

to produce substantial lightening than either argon or CO2

laser treatment The odds of an excellent results were about

50% higher with cryosurgery than with CO2 or argon laser

therapy

IPL (intense pulsed light) uses light wavelength and shows

promise to treat lentigines with minimal side effects.5

Clinical improvement of solar lentigines and ephelides with

an intense pulsed light source Kawada A, Shiraishi H, Asai,

M, et al Dermatol Surg 2002; 28:504–508

A study of intense pulsed light (IPL) was performed in

patients with solar lentigines and ephelides who received 3 to

5 treatments 40% of patients with solar lentigines displayed

more than 50% improvement and 16% had more than 75%

Transient neonatal pustular melanosis Ramamurthy RS,

Reveri M, Esterly NB, Fretzin DF, Pildes RS J Pediatr 1976; 88(5):831–835

This study evaluated 666 infants within 24 hours of birth The infants were examined for signs of transient neonatal pustular melanosis (TNPM) (vesicular pustules, ruptured vesiculopustules with collarette of scale surrounding a pig-mented papule, or pigmented macules) There were 23 African-American infants with TNPM of the 515 examined There was only 1 Caucasian infant of the 145 examined Histopathologic exam was performed on 6 specimens Wright stain demon-strated polymorphonuclear cells, cellular debris and few to no eosinophils The etiology of the disease was not established TNPM is a self-limited, benign condition requiring no therapy

Reassure the parents The remaining vesiculopustules will resolve within 24–48 hours However, the hyperpigmented macules will fade slowly over the coming weeks to months.

Part 2 Pigmentary Disorders

Hypomelanosis of Ito (HI), also known as ‘incontinentia

pig-menti achromians’ is a neurocutaneous disorder which

mani-fests as streaky, linear, coil-like or patchy macules that can

occur on any part of the body Researchers believe the

condi-tion occurs as a result of various genetic anomalies within the

same individual; mosaicism, chimerism, post-zygotic

muta-tions, or X chromosome inactivations have all been

impli-cated.1 The lesions often follow the lines of Blaschko, which

are swirl-like patterns that form around the extremities and

trunk (Fig 11.1).2 Diagnosis is typically made in infancy and

characterized by the aforementioned lesions Clinical

suspi-cion should alert the physician to involvement of other organ

systems.3

Ruiz-Maldonado et al established diagnostic criteria for

Hypomelanosis of Ito:4

• Major criteria

– Congenital or early-acquired non-hereditary cutaneous

hypopigmented linear streaks or patches involving more

than two body segments

– One or more nervous system or musculoskeletal system

anomalies

• Minor criteria– Two or more congenital malformations other than nervous system or musculoskeletal system

– Chromosomal anomalies

Diagnosis can be made with one major or minor criterion

or two minor criteria

The major systemic manifestations of the disease are vast and can be categorized into cutaneous and extra-cutaneous which include cephalic, neurological, oral, musculoskeletal, ophthalmologic, cardiac and urogenital Neurologic abnor-malities often accompany HI and have been reported in up to 40% of cases, though this number varies throughout the litera-ture.5 Neurologic manifestations in HI have been attributed to abnormal migration of nerve cells during development.6 In a case series involving 76 children, the following central nervous system abnormalities were noted:7

• mental retardation observed in 57%

• hypotonia with pes valgus/genu valgus in 18%

• only 22% had a normal intelligence level (IQ > 85)

Non-neurologic changes including multiple dental cusps that protrude from the crowns of both deciduous and perma-nent incisors are considered typical oral manifestations of IH.8Changes in hair color, trichorrhexis and alopecia have been reported.9

TreatmentCurrently there is no specific treatment for HI Camouflage may be employed for cosmetic concerns Camouflage make-up found in the USA, that is water resistant includes Dermablend,

Commonly encountered pitfallsHypomelanosis of Ito may be confused with the condition incontinentia pigmenti Care must be taken to accurately distinguish between these two disorders The diagnosis and management of this condition is multidisciplinary (involving pediatricians, neurologists, dentists and geneticists) and it is a primary role of the dermatologist to assist in accurate diag-nosis of the condition Since the cutaneous manifestations of hypomelanosis of Ito pose no risk to the patient, the focus must be upon the management of the extra-cutaneous manifestations.

Special management & counseling considerationsThe management of hypomelanosis of Ito is limited to cos-metic camouflage of the lesions

References

1 Donnai D, Read AP, McKeown C Hypomelanosis of Ito: a tion of mosaicism or chimerism J Med Genet 1988; 12:809–818.

manifesta-2 Dermnet NZ ito.html [Accessed September 15, 2009].

http://www.dermnet.org.nz/systemic/hypomelanosis-3 Schwartz MF, Esterly NB, Fretzin DF, Pergament E, Rozenfeld IH Hypomelanosis of Ito (incontinentia pigmenti achromians): a neuro- cutaneous syndrome J Pediatr 1977; 90:236–240.

4 Ruiz-Maldonado R, Toussaint S, Tamayo L, Laterza A, Del Castillo V Hypomelanosis of Ito: diagnostic criteria and report of 41 cases Pediatr Dermatol 1992; 9(1):1–10.

5 Fleury P, Dingemans K, de Groot WP, Oranje AP, Voute PA, Woerdeman

MJ, et al Ito’s hypomelanosis (incontinentia pigmenti achromians): a review of four cases Clin Neurol Neurosurg 1986; 88:39–44.

6 Fujino O, Hashimoto K, Fujita T, Enokido H, Komatsuzaki H, Asano

G, et al Clinico-neuropathological study of incontinentia pigmenti achromians – an autopsy case Brain Dev 1995; 17(6):425–427.

7 Pascual-Castroviejoa I, Rochea C, Martinez-Bermejo A, Lopez-Martin

V, Tendero A, et al Hypomelanosis of ITO A study of 76 infantile cases Brain Dev 1998; 20:36–43.

8 Happle R, Vakilzadeh F Hamartomatous dental cusps in sis of Ito Clin Genet 1982; 1:65–68.

hypomelano-9 Ruggieri M, Pavone L Topical review Hypomelanosis of Ito: clinical syndrome or just phenotype? J Child Neurol 2000; 15:635–644.

10 Olson LL, Maria BL Hypomelanosis of Ito In: Maria BL, ed Current management in child neurology 3rd edn Hamilton & London: BC Decker; 2005:476–478.

Covermark and Cover FX In cases with extracutaneous

mani-festations, such as neurological involvement, follow-up with a

specialist is recommended.10 The skin lesions require no

special treatment

Hypomelanosis of Ito Olson LL, Maria BL In: Maria BL, ed

Current management in child neurology, 3rd edn Hamilton

& London: BC Decker; 2005:476–478

In this paper, Olsen et al specify that there is no particular

treatment for HI However, referral to a neurologist for

evalu-ation and management is essential as almost 30% of patients

with HI have refractory epilepsy

Hypomelanosis of Ito Ratz J, Gross N http://emedicine.

medscape.com/article/1068339-treatment [accessed

Septem-ber 15, 2009]

Ratz et al state that there is no specific treatment for the

cutaneous manifestations of HI Specialty care and genetic

counseling should be part of a comprehensive management

plan

Figure 11 1: Hypomelanosis of Ito Note the S-shaped pattern of the

hypopigmented streaks on the flank and abdomen because the lesions are

following Blaschko’s lines (From Bolognia, Dermatology, 2e, Mosby Inc , copyright

Elsevier 2008 )

Hypopigmented

cutaneous T-cell

lymphoma

Of the various types of cutaneous T-cell lymphoma, mycosis

fungoides (MF) is the most common Clonally expanded,

epi-dermotrophic T lymphocytes on the skin characterize this

dis-order.1 The classic types of MF are patch, plaque, and tumor;

however, there are several atypical variants that exist Some examples of these are hypopigmented, psoriasiform, erythro-dermic, follicular, noduloulcerative, ichthyosiform, poikilo-dermatous, morphea and purpuric types.2 The cause of MF is still unknown although a viral etiology is debated.3 Mycosis fungoides has an estimated incidence of 0.4 per 100 000 persons.4

The hypopigmented variant of MF is characterized by the presence of hypopigmented patches as the prime manifesta-tion of the disease.5 It can also be associated with erythema-tous patches, plaques, or tumors (Figs 11.2, 11.3).3 Though typically described in darker skinned individuals (Fitzpatrick skin types IV–V), the disease has also been reported in

11 Hypopigmented Disorders • Hypopigmented cutaneous T-cell lymphoma

Hypopigmented variant of mycosis fungoides: demography, histopathology, and treatment of seven cases Lambroza E,

Cohen SR, Phelps R, et al J Am Acad Dermatol 1995; 32:987–993

Case report of 7 patients with brown or black skin (mean age of 36) in whom 6 treated with PUVA had rapid induction and complete repigmentation The authors believe that PUVA

is first line treatment for hypopigmented MF

Hypopigmented mycosis fungoides in a 20-year-old Saudi woman with fair skin Al-Ratrout JT, Al-Nazer M, Ansari NA

Indian J Dermatol 2006; 51:115–117

Case report of a Saudi woman with skin type IV who responded well to PUVA therapy The authors suggest close follow-up as certain cases of hypopigmented MF can behave aggressively

Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up Herrmann JJ, Hurria A, Kuzel

TM, et al J Am Acad Dermatol 1995; 33:234–242

A clinical trial in which the effectiveness and side-effect profile of long-term use of PUVA to treat early-stage MF was compared to previously reported topical therapies 82 patients with early-stage MF were treated with PUVA, followed by an observation period of 2 months to 15 years (median, 43 months) in which clinical and histologic features were the focus 95% (78) of the subjects showed response, with 65% (53 subjects) clearing of all clinical and histologic signs of disease In a non-randomized comparison with previously reported data for other topical therapies, the efficacy and side-effect profile of PUVA compared favorably

Hypopigmented mycosis fungoides Bahlouli Z,

Blanchet-Bardon C, Chemaly P, Dubertret L, Flageul B, Robert C Ann Dermatol Venereol 1995; 122:704–706

In this rare clinical trial, a 28-year-old woman developed, over a 10-year period, non-infiltrated hypopigmented and discrete squamous macules throughout her entire body Based on pathologic evidence of epidermotropic lymphocyte infiltration, the diagnosis of mycosis fungoides was made The subject was treated with PUVA laser therapy The use of this treatment lead to rapid regression of the lesions and proved effective

Mechlorethamine

Hypopigmented mycosis fungoides: a report of 7 cases and review of the literature Stone ML, Styles AR, Cockerell CJ,

Pandya AG Cutis 2001; 67:133–138

Case report of 7 patients with hypopigmented MF treated with mechlorethamine The mean age was 35 years at disease onset, with a mean of 5.5 years’ duration of illness before presentation All of the patients were Fitzpatrick skin type IV

or V Treatment with topical nitrogen mustard produced repigmentation in 4 of 6 patients

Figure 11 2: Hypopigmented cutaneous T-cell lymphoma

Figure 11 3: Hypopigmented cutaneous T-cell lymphoma (From Johnson, Moy,

White: Ethnic Skin – Medical and Surgical, Mosby Inc , copyright Elsevier 1998 )

Caucasians.3 In a study in Pakistan, 21.3% of the MF patients

had the hypopigmented variety.2 Immunohistochemical

analysis of hypopigmented MF lesions demonstrates

malig-nant epidermotropic CD8+ T lymphocyte clone infiltration.2

Treatment of hypopigmented MF follows that of classic

early-stage MF (IA, IB) Modalities include topical

corticoster-oids, topical mechlorethamine, UVB, and PUVA.6 As opposed

to classic MF, the literature suggests that the treatment of

choice for the hypopigmented variant appears to be PUVA

Narrowband ultraviolet B (UVB)

Narrowband ultraviolet B phototherapy to clear and tain clearance in patients with mycosis fungoides Ayhan M,

main-Boztepe G, Erkin G, Kolemen F, Sahin S J Am Acad Dermatol 2005; 53:242–246

The purpose of this study was to retrospectively evaluate the data obtained from 14 subjects (10 male, 4 female; age range, 28–74 years) who received narrowband UVB to treat MF Although rapid recurrences after discontinuation of therapy appear to interfere with its efficacy, optimal maintenance schedules for prolonged relapse-free intervals are not discussed

in the literature 78% (11 of 14 subjects) showed complete response after a mean of 25 treatments 10 of the 11 subjects who showed complete response were followed for a median

of 22 months after showing signs of complete response The protocol outlined maintenance of narrowband UVB therapy regimen lasting 18 months, which 8 subjects followed No subject showed signs or symptoms of a relapse during this maintenance regimen

Hypopigmented mycosis fungoides in a child successfully treated with UVA1-light Roupe G Pediatr Dermatol 2005;

22:82

Treatment with UVA-1 light has been used successfully in a child to treat hypopigmented MF Recently, NBUVB has also proven to be a safe and easily administered alternative therapy for early-stage MF However, lower response rates have been seen in patients with higher Fitzpatrick skin phototype, pos-sibly because of the photoprotective effect of melanin and also because of the longer disease duration in these patients.7

Commonly encountered pitfallsSince MF is a disease that often progresses slowly, diagnosis may require multiple biopsies over time If histopathologic findings are equivocal, close collaboration with the dermat-opathologist is recommended.8

Special management & counseling considerationsThis disease may follow a benign course.9 Patients may expect

a good response to therapy, though they must be warned that recurrences are common

fun-3 Ardigo M, Borroni G, Muscardin L, et al Hypopigmented mycosis fungoides in Caucasian patients: a clinicopathologic study of 7 cases

J Am Acad Dermatol 2003; 49:264–270.

4 Duvic M, Cather J Emerging new therapies for cutaneous T-cell phoma Dermatol Clin 2000; 18:147–156.

lym-Topical mechlorethamine therapy for early stage mycosis

fungoides Halperin PS, Ramsay DL, Zeleniuch-Jacquotte A

J Am Acad Dermatol 1988; 19:684–691

117 patients with mycosis fungoides were treated with

topical mechlorethamine hydrochloride In subjects with stage

I disease, the probability of achieving a clinically apparent

remission was 75.8%; in subjects with stage II disease, 44.6%;

in subjects with stage III, 48.6% The median time for relapse

was 44.5 months Subjects with stage I achieved complete

remission sooner (median 6.5 months) than stage II (median

41.1 months) or stage III (median 39.1 months) disease When

compared with the results of other treatments for early stage

MF, these findings were favorable

Imiquimod

Treatment of patch and plaque stage mycosis fungoides

with imiquimod 5% cream Aeling JL, Chapman JT, Deeths

MJ, Dellavalle RP, Zeng C J Am Acad Dermatol 2005;

52:275–280

6 patients with stage IA to IIB MF were treated with topical

imiquimod 5% cream 3 times per week for 12 weeks in this

open-label pilot study Index lesions were biopsied pre- and

post-treatment, and up to 4 additional treated lesions were

monitored for 16 weeks 3 of 6 patients had histologic

clear-ance of disease in index lesions, and also demonstrated

sig-nificant improvement in the clinical scores for all treated

lesions A fourth patient had 2 of 4 lesions respond clinically

Application site reactions were limited to those patients

responding to treatment

Corticosteroids

Topical corticosteroids for mycosis fungoides Zackheim HS,

Kashani-Sabet M, Amin S Arch Dermatol 1998; 134:949–954

79 patients with patch or plaque stage of mycosis fungoides

were treated with class I to III corticosteroids 51 of these

patients were stage T1 (less than 10% of skin involved) and 28

were stage T2 (10% or more of skin involved) 75 patients had

patch-stage and 4 had plaque-stage disease as determined by

histological examination Of the stage T1 patients, all used

class I corticosteroids, and 4 (8%) also used class II or III

corticosteroids Of the stage T2 patients, 19 (68%) used class

I and 12 (43%) used class II or III compounds Some patients

used more than one class of corticosteroid 32 (63%) of stage

T1 patients achieved complete remission and 16 (31%)

achieved partial remission, for a total response rate of 48

(94%) The remission rates for stage T2 patients were 7 (25%),

16 (57%), and 23 (82%), respectively 39 patients achieved

clinical clearing

Second-Line Therapies

Narrowband ultraviolet B (UVB) C

11 Hypopigmented Disorders • Hypopigmented sarcoidosis

in general medicine 4th edn New York: McGraw-Hill; 1993: 1285–1307.

8 Gathers RC, Scherschun L, Malick F, Fivenson DP, Lim HW Narrowband UVB phototherapy for early-stage mycosis fungoides J Am Acad Dermatol 2002; 47:191–197.

9 McNiff JM Mycosis fungoides and variants http://uscap.flsi.com/95th/ pdf/companion21h1.pdf [Accessed February 23, 2010]

5 Al-Ratrout JT, Al-Nazer M, Ansari NA Hypopigmented mycosis

fun-goides in a 20-year-old Saudi woman with fair skin Indian J Dermatol

2006; 51:115–117.

6 El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, et al Hypopigmented

mycosis fungoides: frequent expression of a CD8+ T-cell phenotype

Am J Surg Pathol 2002; 26(4):450–457.

7 Heald PW, Edelson RL Lymphoma, pseudolymphoma and related

conditions In: Fitzpatrick TB, Eisen AZ, Wolff K, et al ed Dermatology

Figure 11 4: Hypopigmented, macular (Philadelphia) sarcoid (From Johnson, Moy,

White: Ethnic Skin – Medical and Surgical, Mosby Inc , copyright Elsevier 1998 )

Hypopigmented

sarcoidosis

There are several distinct cutaneous manifestation of systemic

sarcoidosis including hypopigmented sarcoidosis (Chapter 5)

This variant presents as hypopigmented macules, papules

or nodules, typically found on the extremities (Fig 11.4)

Although the etiology of sarcoidosis is unknown, an

autoim-mune etiology has been theorized Hypopigmented

sarcoido-sis has been documented almost exclusively in individuals

of African lineage and its presence may herald systemic

sarcoidosis.1

Histologically, lesions can reveal the classic non-caseating dermal granulomas typically found in sarcoidosis although there are some lesions that do not reveal granulomas.2Electron microscopy studies show possible damage to melanocytes and questionable melanosome transfer abnor-malities in areas of hypopigmented sarcoidosis.3

Diagnosis is clinical, though due to its rarity, a biopsy will more than likely be required More importantly, as Westerhof

et al points out,4 sarcoidosis should be suspected when a patient presents with hypopigmented macules on the extremi-ties and extradermal evidence of a systemic process such as pulmonary abnormalities.4,5

Treatment

8-Methoxypsoralen and long wave ultraviolet light E

Treatment of hypopigmented sarcoidosis with methoxypsoralen and long wave ultraviolet light Patterson

8-JW, Fitzwater JE Int J Dermatol 1982; 21(8):476–480.Case report of facial lesions treated three times per week with 8-methoxypsoralen and UV light The hypopigmented areas re-pigmented after 8 months of therapy

5 Patterson JW, Fitzwater JE Treatment of hypopigmented sarcoidosis with 8-methoxypsoralen and long wave ultraviolet light Int J Dermatol 1982; 21(8):476–480.

Pigmented pityriasis alba is an uncommon variant usually confined to the face, and associated with dermatophyte infec-tion.2 The typical lesion is described as a central zone of hyper-pigmentation, usually bluish, surrounded by a moderately scaly halo.2 This halo varies in diameter.2

Extensive pityriasis alba is another uncommon variant of pityriasis alba This variant typically affects more females than males It is also differentiated by its lack of an inflammatory phase prior to onset As its name suggests, extensive pityriasis alba is widespread and occurs symmetrically.3

Emollients and mild topical corticosteroids have a tendency

to speed up the repigmentation of lesions of pityriasis alba, although their efficacy has been proven to be limited.4

Figure 11 5: Pityriasis alba in a female patient

Figure 11 6: Pityriasis alba (From Johnson, Moy, White: Ethnic Skin – Medical

and Surgical, Mosby Inc , copyright Elsevier 1998 )

Pityriasis alba

Pityriasis alba has been referred to as a variant of atopic

der-matitis or eczema in its mild form The condition is not limited

by race, but is more common and is cosmetically more

appar-ent and difficult to treat in darker skinned patiappar-ents.1 A red,

pink or skin colored irregular plaque, that is rounded or oval

in shape, characterizes an individual pityriasis alba lesion

These lesions typically have indistinct margins with fine

lamel-lar or branny scaling (Fig 11.5) Lesions observed usually

range from 0.5 to 2 cm in diameter, however it is not

uncom-mon to observe larger patches on the trunk Pityriasis alba is

common among children (Fig 11.6) In children it occurs

more commonly on the trunk and limbs; only 20% of children

diagnosed with the disorder have involvement of the arms,

± 0.00 at week 9 for group A The statistical difference between both groups was significant on all three assessments for hypo-pigmentation (p < 0.001), and for pruritis on week 6 and 9 assessments (p < 0.05) 11.5% of the subjects from group A reported a mild transient sensation of burning All subjects in group A reported they were completely satisfied or just satis-fied with the treatment, compared to only 50% of the subjects from group B Tacrolimus ointment 0.1% appears to be a effec-tive and safe treatment for pityriasis alba

An exploratory study to determine the efficacy of 1% crolimus cream in the treatment of pityriasis alba Fujita

pime-WH, McCormick CL, Parneix-Spake A Int J Dermatol 2007; 46(7):700–705

This open-label, single-arm study was designed to mine the efficacy and safety of 1% pimecrolimus cream in the treatment of pityriasis alba 10 subjects (ages 12–35) with

deter-11 Hypopigmented Disorders • Vitiligo

sone to a placebo in 29 subjects The subjects were asked to apply the medication 3 times daily for 1 month The combina-tion therapy proved to have favorable results with a highly significant difference compared with the placebo

Oral methoxsalen photochemotherapy of extensive sis alba Jaber LA, Kurban AK, Zaynoun S J Am Acad Dermatol

of the cohort, achieved marked improvement after 15 weeks

4 Janniger CK, Lin RL Pityriasis alba Cutis 2005; 76:21–24.

Fitzpatrick skin types IV and V were enrolled into this 3-month

study and instructed to apply 1% pimecrolimus cream to the

hypopigmented areas twice daily for 3 months Visit schedules

included a baseline visit and 3-, 6- and 12-week evaluations

Subjects were also supplied facial moisturizers with SPF 15

sunscreen and mild soap-free cleansers to supplement their

treatment 9 of 10 subjects completed the study and marked

improvement of uneven skin tone and complete resolution of

scaling were apparent at the 3-week visit Near-complete

reso-lution of uneven skin tones was observed at the 12-week visit

1% pimecrolimus cream was found to be safe and effective in

the treatment of pityriasis alba in children and adults

Figure 11 7: Perioral vitiligo (From Johnson, Moy, White: Ethnic Skin – Medical

and Surgical, Mosby Inc , copyright Elsevier 1998 )

Second-Line Therapies

2% coal tar, 1% di-iodohydroxyquinolin, 0 5%

hydrocortisone

AOral methoxsalen photochemotherapy C

Treatment of pityriasis alba with a combination of coal tar,

di-iodohydroxyquinolin and hydrocortisone Gonzalez OA,

Vargas OF Med Cutan Ibero Lat Am 1980; 8:69–72

This double-blind trial compared the use of a combination

of 2% coal tar, 1% di-iodohydroxyquinolin, 0.5%

hydrocorti-Vitiligo

Vitiligo is a progressive, hypopigmentary disorder

character-ized by the absence of epidermal melanocytes and melanin

and thus absence of pigment The scalp, neck and face are the

areas most commonly involved with vitiligo Initial lesions

can be seen on the extremities, particularly the face, hands

and feet (Fig 11.7) The condition can exact a heavy

psycho-logical toll on those afflicted, and is a common source of

embarrassment

Vitiligo has a worldwide incidence of 1% and many patients

have a familial history of the disease.1,2 Curiously, involved

areas are ones routinely subjected to trauma with activities of

daily living

Many of the common sites of occurrence are areas subjected

to repeated trauma or sun exposure such as:3

The lesions can be unilateral and follow a dermatomal

distribution, though typically they present symmetrically.4

Mucosal involvement can be seen, especially in generalized

vitiligo and the disease has an affinity for periorificial surfaces

in such cases (Fig 11.8).5 Depigmentation of hair in nous areas, (leukotrichia) may be seen (Figs 11.9 & 11.10) Of note, individuals with bilateral (typical) vitiligo have a low incidence of leukotrichia, however those with unilateral (seg-mental) vitiligo have a higher incidence of depigmented hair;

vitiligi-in the latter scenario the disease seems to be more resistant to standard treatments.6

The disorder has been associated with various conditions:4

sur-of melanocytic autoprotective mechanisms, leading to the destruction of the cell.1 Lerner also suggests that neurochemi-cals might inhibit melanocytes.8 Moreover, abnormal concen-trations of catecholamine metabolites have been found in patients with the condition and this imbalance might lead to depigmentation.9

Diagnosis is usually clinical Patients can present with symmetrical, or classic vitiligo, or in a unilateral, atypical fashion A Wood’s lamp can help differentiate vitiligo from hypopigmentary disorders such as pityriais versicolor A biopsy

is in order if diagnosis is unclear Additionally, evaluation

of thyroid function and anemia is appropriate for vitiligo patients

TreatmentTreatment for vitiligo is directed at repigmentation and in progressive or unstable vitiligo, arresting the depigmentation (Fig 11.11) Therefore, treatment strategies for vitiligo must address the type of vitiligo, generalized or localized, stable or progressing, as well as the total amount of body surface area involved It should also take into consideration the part of the body surface area involved.10

The development of guidelines for the treatment of vitiligo

Njoo MD, Westerhof W, Bos JD Arch Dermatol 1999; 135(12):1514–1521

This is an extensive review of the literature regarding ment for vitiligo with evidence-based guidelines Meta-analyses were performed on all studies to date (1999), and showed that class III corticosteroids and narrowband UVB (NBUVB) are the most effective and safest therapy for localized and generalized vitiligo

treat-It is interesting in these reviews that patients with vitiligo regarded 75% repigmentation as a cosmetically acceptable level

of repigmentation.

Figure 11 8: Vitiligo in a typical location (From White & Cox, Diseases of the Skin,

A Color Atlas and Text, 2E, Mosby Inc , copyright Elsevier 2006 )

Figure 11 9: Vitiligo with leukotrichia Hairs with in patches of vitiligo often lose

their color (From White & Cox, Diseases of the Skin, A Color Atlas and Text, 2E,

Mosby Inc , copyright Elsevier 2006 )

Figure 11 10: Follicular repigmentation of vitiligo When vitiligo repigments,

it often does so initially around the hair follicles (From White & Cox, Diseases of

the Skin, A Color Atlas and Text, 2E, Mosby Inc , copyright Elsevier 2006 )

11 Hypopigmented Disorders • Vitiligo

and neck or both was seen in 68% of the patients (n = 13) Tacrolimus therapy may be helpful as adjunctive therapy for vitiligo

Treatment of vitiligo with 0.1% betamethasone 17-valerate

in isopropyl alcohol – a double-blind trial Kandil E Br J

Dermatol 1974; 91:457–460

In this study, 19 patients with symmetrically distributed

patches of vitiligo were treated with topical corticosteroids It

was the most effective treatment for localized vitiligo

Meta-analysis of other studies showed that class III topical

corticosteroid was the most effective treatment for localized

vitiligo.

Topical tacrolimus therapy for vitiligo: therapeutic responses

and skin messenger RNA expression of proinflammatory

cytokines Grimes PE, Morris R, Avaniss-Aghajani E, et al J Am

Acad Dermatol 2004; 51(1):52–61

In this prospective, non-randomized, uncontrolled study of

23 patients with vitiligo, variable repigmentation occurred in

81% of the patients (n = 17); 75% repigmentation of the face

‘cobble stoning’; less than 75% of lesions repigmented

Figure 11 11: The evaluation of first choice therapies for vitiligo

BSA = Body Surface Area

Determine site of involvement

As appropriate:

Cosmetic camouflaguePsychological and social support

Exposed sites

< 10% of BSA affected

*Topical calcineurin inhibitors

*Topical corticosteroid agents

*Targeted UVB phototherapy

with or without calcipotriene; with or

without topical calcineurin inhibitors

*Topical agents: 20%

Monobenezyl Ether ofHydroquinone cream

*Combination of topicaldepigmentation agentsand Q-switch Ruby lasertreatment

Unexposed sites

Observation vs

BSA based treatment approach

Randomized, controlled study to identify the optimal quency of 308-nm excimer laser treatments In this study of

fre-14 patients, repigmentation was fastest when treatments were administered three times a week

The use of the 308-nm excimer laser for the treatment of vitiligo Hadi SM, Spencer JM, Lebwohl M Dermatol Surg

2004; 30:983–986

This is a retrospective review of the literature that found that lesions of the hands and feet did not exhibit > 75% repigmen-tation with excimer treatment However, 71.5% of facial lesions, 60% of neck and scalp lesions, and 40% of truncal showed

> 75 % repigmentation using the 308-nm excimer laser

Calcipotriene and vitiligo Vásquez-López F, López-Escobar

M, Pérez-Oliva N Arch Dermatol 2003; 139:1656–1657.This was an open pilot study of 10 patients with vitiligo The efficacy and safety of PUVA with topical calcipotriene was assessed Repigmentation was not significant

Combination of narrowband UV-B and topical calcipotriene

in vitiligo Dogra S, Parsad D Arch Dermatol 2003; 139:393.

A case report of a patient who was treated with NBUVB and calcipotriene in vitiligo of the lower extremities The results of this single case demonstrated that NBUVB with cal-cipotriene worked faster in repigmentation Calcipotriene may act in vitiligo either by 1,25-dihydroxyvitamin D3 receptors on melanocytes or by modifying defective calcium homeostasis

in the epidermal unit

Depigmentation of vitiligo should be reserved for tory, stable vitiligo of greater than 80% of body surface area (Fig 11.12)

refrac-A systematic review of autologous transplantation methods

in vitiligo Njoo MD, Westerhof W, Bos JD, et al Arch

Derma-tol 1998; 134:1543–1549

The development of guidelines for treatment of vitiligo was

based on three systematic reviews of the literature combined

with the results of two questionnaires, interviews with

poten-tial users of the guidelines, three interactive expert meetings

and one local expert meeting

Other forms of surgical repigmentation include autologous

suction blister grafting The most successful of these methods

was performed in stable segmental vitiligo The highest success

rates were achieved with split-thickness skin

The transplantation of monoculture in in-vitro cultures of

autologous epidermis or pure melanocytes involves

trans-planting auto logous thin sheets of epidermis This may involve

sheets of thin epidermal tissue, or pure melanocytic tissue

which have been previously cultured in-vitro This is

sub-sequently followed by compression with bandages after

grafting

In the study of culturing techniques, no significant results

can be drawn due to the small numbers of patients who

have been enrolled The transplantation method must take

into account disease characteristics such as disease stability

and the expertise of the physician

Randomized double-blind trial of treatment of vitiligo:

efficacy of psoralen–UV-A therapy vs narrowband–UV-B

therapy Yones SS, Palmer RA, Garibaldinos TM, Hawk JL Arch

Dermatol 2007; 143(7):906

This was a randomized double-blind placebo control study

comparing narrowband UVB (NBUVB) with psolaren UVA

(PUVA) in 50 patients with vitiligo At the end of the treatment

period (48 treatments), both PUVA and NBUVB demonstrated

excellent responses with repigmentation of vitiliginous areas

but NBUVB showed superior results to PUVA

Targeted phototherapy has been available for the treatment

of vitiligo and includes the 308-nm excimer laser and UVB and

UVA targeted therapy

Topical tacrolimus and the 308-nm excimer laser: a

syner-gistic combination for the treatment of vitiligo Passeron

T, Ostovari N, Zakaria W, et al Arch Dermatol 2004; 140:

1065–1069

Randomized controlled study with 23 patients with a total

of 43 lesions treated with a 308-nm excimer laser alone (n =

4) or in combination with 0.1% tacrolimus ointment (n = 16)

24 treatments were performed and 100% repigmentation was

seen in the combination group, 85% repigmentation in the

excimer laser monotherapy group, and no repigmentation in

the control group However, 75% or greater lesion

repigmenta-tion was seen in 70% of the combined laser and tacrolimus

group, but only 20% of the excimer laser monotherapy

Optimal weekly frequency of 308-nm excimer laser

treat-ment in vitiligo patients Hofer A, Hassan AS, Legat FJ, et al

Br J Dermatol 2005; 152:981–985 Figure 11 12: Incomplete depigmentation with monobenzylether of hydroquinone