Manual of Dermatologic Therapeutics
7th Edition
© 2007 Lippincott Williams & Wilkins
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17
Hyperpigmentation and Hypopigmentation
Manisha J. Patel
I. Definition and Pathophysiology
Patients with pigmentary changes on their skin seek advice primarily for cosmetic reasons; they complain of having either too much or too little pigmentation, or they are unhappy with its distribution. Pigment changes are usually asymptomatic and of no medical consequence. However, they may signify underlying systemic disease. Treatment of diffuse and circumscribed hyper- and hypomelanotic disorders are the focus of this section.
  • Hyperpigmentation
    • Melasma (chloasma) is an acquired reticulated hyperpigmentation found most often on sun-exposed skin of women and men. Historically known as the “mask of pregnancy,” its pathogenesis is now thought to be multifactorial. These factors include genetic predisposition, ultraviolet (UV) light exposure, oral contraceptive use, and pregnancy. Melasma may be found in men or women with no apparent endocrine abnormalities. It is present more frequently in darkly pigmented races.
    • Freckles (ephelides), like melasma, are present only on light-exposed skin; neither is found on mucous membranes. Freckling is genetically determined; usually appears by age 5 to 7 years; and is seen most commonly in redheads, blondes, and other fair-skinned individuals. Paradoxically, there are fewer melanocytes in a freckle than in normal surrounding skin, but those that are present are large and are able to form more melanin than usual. Freckles, like melasma, darken considerably during summertime and may fade almost completely in winter.
    • A lentigo (pl. lentigines) is most often confused with a freckle. These hyperpigmented spots, which may appear at any age, are usually darker than freckles and neither increase in darkness in the summer nor fade in the winter. Histologically, an increased number of melanocytes are present in the basal layer, and the epidermal rete ridges are elongated and clubbed.
      • Solar lentigines (informally and inaccurately known as liver or age spots) appear on sun-exposed surfaces of fair-skinned people, usually in association with other changes from sun damage, including wrinkling, dryness, and actinic keratoses.
      • Lentiginous pigmentation has been observed following prolonged psoralen plus ultraviolet A (PUVA) therapy, although these lesions, as opposed to solar lentigines, display melanocytic cytologic atypia.
      • Lentigines associated with systemic disorders: multiple lentigines, especially if present on the palms, soles, mucous membranes, or non–sun-exposed skin, are often indicative of syndromes with significant internal abnormalities. Examples of such associations are the Peutz-Jeghers syndrome (lentigines, intestinal polyposis, ovarian tumors), the LEOPARD syndrome (lentigines, EKG changes, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation, and deafness), and the LAMB syndrome (lentigines, atrial myxoma, mucocutaneous myxomas, and blue nevi).
      • Mucosal lentigines may occur on the lips, vulva, and penis. Labial melanotic macules occur most commonly on the lower lip of young women.
      • Longitudinal pigmented streaks of the nails are common in darker-skinned individuals. However, they should be examined carefully for the possibility of an acral melanoma. Single pigmented bands, increasing in size with or without pigmentation of the nail fold, should be biopsied.
    • Postinflammatory hyperpigmentation is common in more darkly pigmented persons and is more related to the nature of the insult than to the degree of
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      previous inflammation; it is severe following some conditions, such as thermal burns, and mild after others. There is an increase in epidermal melanin, but melanin granules may also be present in dermal macrophages. Postinflammatory hyperpigmentation may persist for months to years.
  • Hypopigmentation
    • Vitiligo is a common, acquired disease affecting 1% to 2% of the population with women being more affected than men. Fifty percent develop their lesions before the age of 20 and 25%, before the age of 10. Localized or generalized areas of the skin completely lack melanin pigmentation. Melanocytes cannot be detected in depigmented areas, even on inspection by electron microscopy. This finding is in contrast to albinism, in which melanocytes are present but there is little or no pigmentation because of faulty or absent melanin synthesis. The cause of vitiligo is unknown; an abnormal neurogenic stimulus, intrinsic genetic defect of melanocytes, aberrant catecholamine response, an enzymatic self-destruction mechanism involving a deficiency of a melanocytic growth factor, a breakdown in epidermal free radical defense, and an autoimmune mechanism have been postulated as pathogenetic factors. Because of the association with other autoimmune diseases, an autoimmune etiology is favored. Serum of patients with active vitiligo has been found to be cytotoxic to normal melanocytes.
      Vitiligo appears to have a familial incidence of 20% to 30% and is found with increased frequency in patients with endocrinopathies. These include thyroid disease, Addison’s disease, gonadal atresia, and pernicious anemia. In patients with vitiligo, there is also an increased incidence of halo nevi, diabetes mellitus, alopecia areata, and ocular abnormalities. Complete spontaneous repigmentation is rare.
    • Postinflammatory or posttraumatic hypopigmentation may be profound enough to mimic vitiligo but frequently appears as slightly scaly, slightly lighter areas of skin. It is often seen following cutaneous diseases such as psoriasis and atopic dermatitis and in those instances may be related to the inability of altered epidermal cells to accept melanin granules rather than to the decreased production of pigment in melanocytes. Pityriasis alba is found most frequently on exposed areas (e.g., face) in children with atopic backgrounds. Postinflammatory hypopigmentation repigments slowly but may be permanent in rare instances, especially if scarring has occurred.
II. Subjective Data
There are no symptoms associated with melasma, freckles, lentigines, or postinflammatory changes. The depigmented areas of vitiligo sunburn easily.
III. Objective Data
  • Melasma appears on sun-exposed skin as brown, gray, or even blue macules with irregular outlines or in a reticulated pattern on the cheeks, upper lip, and forehead.
  • Freckles (ephelides) are small (usually 2 to 5 mm), pale to dark macules scattered irregularly on the face, shoulders, back, and other sun-exposed areas. There is usually a sharp line of demarcation between freckled and unexposed skin.
  • Lentigines may be the same size as freckles or larger; they may be found anywhere on the cutaneous surface. Solar (“senile”) lentigines are pale to dark-brown macules found on the dorsum of the hand and on the face. They vary in color and size (from millimeters to centimeters in diameter).
  • Vitiligo—There are three subtypes of vitiligo: localized (<20% of the body surface area, either focal or unilateral/segmental); generalized, also known as vitiligo vulgaris; and universal (complete or near complete depigmentation). Segmental vitiligo is much more common in children than adults and tends to spread rapidly within the segment of skin.
    The lesions of vitiligo are completely depigmented except in the rare case of trichrome vitiligo, which has both depigmented and hypopigmented areas. They usually have sharp borders and are found symmetrically over bone prominence such as the wrists and around body orifices (lips, eyes, and anogenital areas). Injury to the skin of these patients may cause a temporary or permanent loss of pigment in that area. Scars, scratch marks, and bruises may therefore heal with no
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    pigment present. Hair growing from vitiliginous skin may or may not be depigmented.
  • Postinflammatory pigment changes vary in size and are present only at the site of previous inflammation and trauma. The degree of hyper- or hypopigmentation may be mild or marked.
IV. Assessment
It is useful to examine pigmentary lesions under Wood’s light (see also Chap. 38, Wood’s Light Examination). When pigment is present in the epidermis, the contrast between normal and hyperpigmented skin is enhanced. When pigment is present in the dermis, the contrast is not enhanced compared with ambient visible light. Thirty percent of patients with melasma will have pigment in the dermis, which makes treatment more difficult.
Patients with generalized lentigines and those with vitiligo deserve a thorough history and physical examination to search for related systemic findings. Patients with vitiligo, especially those in older age-groups, need to be checked periodically for incipient or clinically apparent thyroid disease, particularly hypothyroidism. T4 and thyroid-stimulating hormone (TSH) determinations provide adequate screening. Phenolic germicidal agents present in household and industrial products may cause a chemical depigmentation indistinguishable from that of vitiligo.
V. Therapy
  • Treatment of hyperpigmentation
    • Cryosurgery. Hyperpigmented macules and patches may be removed or their intensity of pigmentation diminished by light cryosurgical freezing (5 to 7 seconds of intermittent freeze) with liquid nitrogen. Melanocytes are more sensitive to cold injury than keratinocytes and may be selectively damaged by this technique.
    • Laser/light therapy. Treatment with the Q-switched ruby, Q-switched alexandrite, and Q-switched Nd:YAG are very effective. Latest studies show that laser with longer pulse width, such as long-pulse Nd:YAG or pulsed dye laser (PDL) may also be helpful. These lasers all target melanocytes and decrease hyperpigmentation, theoretically leaving the skin intact without scarring. However, they also carry a risk of postinflammatory hypo- or hyperpigmentation, scarring, and even keloid formation. Intense pulsed light (IPL) is a noncoherent, filtered, broad-spectrum light (500 to 1,200 nm) emitted from a pulsed flashlamp. IPL and PDL handpieces usually offer larger spot sizes, making them useful for treating large areas.
    • Topical bleaching agents
      • Hydroquinone (HQ) alone. The intensity of pigmentation in melasma, ephelides, lentigines, and the epidermal component of postinflammatory hyperpigmentation may be decreased by the regular application of 2% to 5% HQ cream or lotion b.i.d. for weeks to months. HQ over the counter is usually 2%; 4% is the typical concentration prescribed by dermatologists although pharmacists can mix concentrations up to 10%. HQ is thought to act by (i) competing with tyrosine oxidation by acting as an alternate substrate for tyrosinase, the enzyme that converts tyrosine to melanin and (ii) selective damage to melanosomes and melanocytes. Four to 6 weeks of monotherapy are required before depigmenting effects are seen. The hyperpigmented areas fade more rapidly and completely than the surrounding normal skin. The most common side effects are skin irritation and contact dermatitis which can be treated with topical steroids. A rare side effect is the development of exogenous ochronosis which can be extremely difficult to reverse. It is thought to result from the extended use of HQ, with the greatest risk in dark-complected individuals living in sunny climates. Alternating HQ in 4-month cycles with other depigmenting agents can prevent or reduce side effects.
      • Monobenzyl ether of hydroquinone (MBEH/Benoquin) is melanocidal. It is selectively taken up by melanocytes and metabolized into free radicals that can destroy melanocytes permanently, leading to irreversible depigmentation. As a result, MBEH is usually reserved for generalized depigmentation in patients with extensive vitiligo and should not be used under any other
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        circumstances. This process requires 9 to 12 months of continuous daily application to achieve complete depigmentation.
      • Kligman’s formula. Kligman and Willis in 1975 observed an enhanced efficacy of 5% HQ, 0.1% tretinoin and 0.1% dexamethasone in hydrophilic ointment in the treatment of melasma, ephelides, and postinflammatory hyperpigmentation. In contrast, they noted poor results using each of the aforementioned agents as monotherapies. A similar formulation is available as TRI-LUMA cream (fluocinolone acetonide 0.01%, HQ 4%, tretinoin 0.05%). The medications should be applied once at night and an SPF 30 sunscreen and protective clothing should be worn during the day.
      • Azelaic acid is a naturally occurring dicarboxylic acid derived from Pityrosporum ovale. It is available in strengths of 15% to 20% in the United States by prescription. It is applied b.i.d. for 3 to 12 months and is generally well tolerated.
      • Mequinol (4-hydroxyanisole) is a substrate of the enzyme tyrosinase and acts as a competitive inhibitor of melanogenesis. The combination of mequinol 2% and tretinoin 0.01% is available as Solagé and is indicated for twice-daily dosing.
      • Other treatments that are advocated for the treatment of hyperpigmentation include topical kojic acid, glycolic acid (either in topical preparations or peels in concentrations of 30% to 70%), topical Jessner’s solution, and microdermabrasion. Multiple naturally occurring or alternative agents with potential therapeutic effects include aloesin (derivative of aloe vera), arbutin (found in bearberry fruits), licorice extract (Glabridin), soy, and vitamin C. These treatments have not been supported by rigorous clinical studies and represent a more theoretical and anecdotal experience.
      • Combination therapy. Numerous formulations are available on the market combining HQ together with sunscreens, vitamins, and α-hydroxy acids. Some of these products include Lustra, Lustra-AF, Lustra-Ultra, Glyquin, Eldoquin, Eldoquin Forte, Epiquin, and Soloquin Forte.
    • Sun protection. Because the ability of the sun to darken lesions is much greater than that of HQ to “bleach” the pigment, strict avoidance of sunlight is imperative. Although sunscreens help, even visible light will cause some pigment darkening, and to be totally adequate, sun protection must be opaque (e.g., Clinique Continuous Coverage). Some HQ products are available in an opaque base (Eldopaque, Eldopaque Forte) or with nonopaque sunscreens (Solaquin). Alternatively, a broad-spectrum sunscreen with sun protection factor (SPF) 15 or greater may be applied followed by makeup of the patient’s choice.
  • Treatment of vitiligo. There are multiple methods that may be useful, including repigmentation methods, in addition to depigmentation in patients with widespread disease. All patients with vitiligo should practice aggressive sun protection measures. Avoidance of the sun during peak hours and/or conscientious use of broad-spectrum sunscreens should be stressed in all patients. Sun avoidance helps fade normal pigmentation in the fair-skinned individual, thereby making the vitiligo less noticeable. Patients with vitiligo should routinely use sunscreens with SPF 15 or greater that are effective against UVB when outside to prevent sunburn in nonpigmented areas.
    • Psoralen plus ultraviolet A (PUVA)
      • Systemic psoralen plus phototherapy attempts to repigment skin with the topical or systemic use of psoralen compounds. As a general guide, if the vitiliginous skin is <6 cm2 (the size of a quarter or half-dollar), topical psoralens may be used; if a large portion of the body surface is involved, systemic psoralens and sunlight are indicated; if the area involved is extremely widespread (>50% of the body surface area), depigmentation with MBEH may be considered (see preceding text).
        Psoralen compounds are tricyclic furocoumarin–like molecules found naturally in a variety of plants throughout the world and are also produced synthetically. They radically increase the erythema response of skin to long-wave ultraviolet light (UVA) after either topical application or
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        systemic administration. Seventy-five percent of patients will have partial repigmentation when treated twice a week for more than a year. For this reason, therapy must be initiated gradually and monitored carefully.
        The most commonly used oral psoralen is 8-methoxypsoralen (8-MOP). 8-MOP (Oxsoralen-Ultra) at a dose of 0.4 to 0.6 mg/kg, taken at least 1 hour before carefully monitored indoor UVA light source achieves some repigmentation in 70% of patients. Pigment reappears first as dots around hair follicles and then spreads slowly, becoming confluent. Dots of pigment should be seen within 25 exposures with facial lesions and 50 exposures with involvement elsewhere; if not, treatment should be discontinued. Treatments should be given one to two times weekly and never for 2 days in a row. Patients should be instructed to wear plastic-lens sunglasses known to block UVA before and after exposure on treatment days (UVA passes through glass). On nontreatment days, sun exposure should be restricted for patients on 8-MOP. Following treatment, a sunscreen effective against UVA should be applied to all exposed skin; this will provide partial protection. Those who sunburn easily may benefit from using a UVB sunscreen all day, even during treatment. Prolonged exposure to sunlight beyond the treatment period should be avoided for 8 hours after the medication has been ingested. Nontender, minimal pink coloration of the patches of vitiligo is acceptable, but if increasing redness develops, discontinue treatment until only faint pinkness remains.
        To be successful, therapy must continue for 9 to 18 months. The age of the patient and duration of vitiligo do not affect the response rate. Lesions on the face and neck repigment more easily than those over an osseous prominence such as the dorsa of the hands, the elbows, and the knees. If treatment is discontinued before an area has completely filled in, the lesion is likely to gradually become white again. Psoralen therapy also increases the tolerance of vitiligo skin to sunlight, perhaps through thickening of the stratum corneum.
        Psoralens may produce pruritus, nausea, corneal burns, and an acute and painful erythema. Long-term therapy with PUVA may produce premature aging, cataracts, photoallergic dermatitis, freckling of the skin, and an increased risk of skin cancer, including melanoma.
      • Bath PUVA. Dilute 1 mL of 8-MOP solution (1 mg/mL standard solution) in 2 L of warm water in a basin or dilute 10 mL of 0.1 mg/mL trioxsalen (trimethylpsoralen in 95% ethyl alcohol) in 2 L of warm water which must be agitated during soaking. The patient soaks the affected area of the body to be treated for 15 minutes, pats the skin dry, and then protects the nonaffected skin from the UV light. The initial dose for bath PUVA for all skin types is 0.5 J/cm2 of UVA. The frequency is one to two times a week.
      • Paint PUVA. The patient should receive a compounded lotion containing 0.01% of 8-MOP or if prepared using an ointment base, the concentration should be 0.1% of 8-MOP. The compound is applied to the affected skin for 30 minutes. The initial dose of UVA for paint PUVA is 0.5 J/cm2. After treatment, the area should be washed and protected from ambient UV exposure. The frequency is one to two times a week.
    • Narrowband UVB (NB-UVB) has demonstrated effectiveness as monotherapy (1). The initial starting dose is approximately 300 mJ/cm2 with increments of 10% to 20% at each subsequent exposure. Treatment is administered 2 days a week. The advantages of NB-UVB over PUVA include shorter treatment times; no drug costs; reduced phototoxic reactions; and use in children, pregnant women, and patients with hepatic and kidney dysfunction.
      • The excimer laser (intense NB-UVB light at a wavelength of 308 nm) appears to be effective in repigmentation after at least six sessions. However, the results are temporary and must be maintained with retreatment.
    • Other phototherapies. Khellin and phenylalanine plus UVA have also been proposed for the treatment of vitiligo. There have been conflicting reports
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      regarding these treatment strategies, including concern of hepatic toxicity with khellin, and, therefore, these are not considered first-line therapies for vitiligo (2). In addition, a combination of topical pseudocatalase and UVB has demonstrated conflicting results (3,4). Further studies are necessary.
    • Depigmenting the surrounding skin to blur the margins of the lesion or removing all remaining pigmentation in extensive cases may lead to cosmetic improvement. Blurring of the margins of the lesion may be attempted with HQ compounds. Permanent removal of pigment requires the use of MBEH (Benoquin) cream.
    • Camouflage the lesions using Covermark or Dermablend; Dy-O-Derm, a stain that contains aniline dyes and dihydroxyacetone; Vitadye, a cosmetic cover containing FD and C dyes and dihydroxyacetone; or quick-tan preparations containing dihydroxyacetone. These latter agents do not provide protection against sunburn, and psoralen phototherapy can take place through such stains.
      An aloe-based synthetic melanin product (Melasyn) is helpful in covering depigmented areas of vitiligo. This product offers protection against UV light and can be made waterproof by applying a spray-on sealant. (Vitiligo Solution Inc http://www.vitiligosolution.com.)
    • Topical immunomodulators may induce some repigmentation in up to 90% of patients. Application of 0.1% tacrolimus ointment twice daily for 2 months has been shown to be nearly as effective as superpotent topical corticosteroids and does not carry with it the risk of adverse effects (5,6).
    • Topical and intralesional corticosteroids have yielded very mixed results in the treatment of vitiligo, although for localized lesions, a trial of a potent topical steroid administered on a b.i.d. basis is worthwhile. The potential adverse reactions—particularly atrophy, glaucoma (if used near the eyes), and, for intralesional therapy, treatment-related depigmentation—must be kept in mind. Treatment is continued for 3 to 4 months. When topical corticosteroid treatment is contraindicated, calcipotriol and tacrolimus therapy can be considered.
      Low-dose oral corticosteroids (0.3 mg/kg/day) over a 4-month course were found to be helpful in patients with actively spreading vitiligo (7).
    • Permanent dermal micropigmentation using a nonallergenic iron oxide pigment can permanently tattoo recalcitrant areas of vitiligo (i.e., hands, perioral region, and the hairline).
    • Surgical techniques to transplant autologous melanocytes or cultured epidermal autografts to nonpigmenting areas have been found promising (8,9). Epithelial sheet grafting (after dermabrasion or suction blister formation), minigrafting, and “flip-top” procedure have been successful in stable vitiligo patients (10).
  • Postinflammatory hypopigmentation. Treatment is usually neither necessary nor rewarding. If any inflammation persists, antiinflammatory therapy is obviously advisable. Otherwise, the best approach is education, reassurance, and, if appropriate, concealing cosmetics.
References
1. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997;133:1525–1528.
2. Siddiqui AH, Stolk LM, Bhaggoe R, et al. L-Phenylalanine and UVA irradiation in the treatment of vitiligo. Dermatology 1994;188:215–218.
3. Patel DC, Evans AV, Hawk JL. Topical pseudocatalase mousse and narrowband UVB phototherapy is not effective for vitiligo: an open, single-centre study. Clin Exp Dermatol 2002;27:641–644.
4. Schallrueter KU, Wood JM, Lemke KR, et al. Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short-term UVB exposure: a case study on 33 patients. Dermatology 1995;190:223–229.
5. Silverberg NB, Lin P, Travis L, et al. Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases. J Am Acad Dermatol 2004;51(5):760–766.
6. Lepe V, Moncada B, Castanedo-Cazares JP, et al. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol 2003;139(5):581–585.
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7. Kim SM, Lee H-S, Hann S-K. The efficacy of low-dose oral corticosteroids in the treatment of vitiligo patients. Int J Dermatol 1999;38:546–550.
8. Falabella R, Arrunategui A, Barona MI, et al. The minigrafting test for vitiligo: detection of stable lesions for melanocyte transplantation. J Am Acad Dermatol 1995;32:228–232.
9. Kim HU, Yun SK. Suction device for epidermal grafting in vitiligo: employing a syringe and a manometer to provide adequate negative pressure. Dermatol Surg 2000;26:702–704.
10. McGovern TW, Bolognia J, Leffell DJ. Flip-top pigment transplantation: a novel transplantation procedure for the treatment of depigmentation. Arch Dermatol 1999;135(11):1305–1307.
Suggested Readings
Guerra L, Capurro S, Melchi F, et al. Treatment of “stable” vitiligo by timed surgery and transplantation of cultured epidermal autografts. Arch Dermatol 2000;136:1380–1389.
Halder RM, Young CM. New and emerging therapies for vitiligo. Dermatol Clin 2000;18:79–89.
Nijoo MD, Westerhof W, Bos JD, et al. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999;135:1514–1521.
Nijoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000;42:245–253.
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