Disorders of Pigmentation

Leslie Baumann, MD
pigmentation disorders are not usually considered cosmetic problems. However,
almost every female who worries about -rinkles and aging also complains about
pigmentation concerns. Like acne, disorders of pigmentation cause significant
jtress and embarrassment, so the treatment options should be understood by every
cosmetic dermatologist. In this chapter, the discussion focuses on the pigmentary
conditions most likely to be seen by a cosmetic dermatologist. The wide range of
dyschromias that are more pathological in nature, md that are usually more rare,
are beyond the scope of this chapter. This is not to suggest that the cosmetic
dermatologist should not consider the vast, evolving area of research on etiology
of pigmentary anomalies. Indeed, the fact that manufacturers of several over-the-
counter cosmetic products promise that their products will lighten dark spots
makes it especially important that cosmetic dermatologists understand the
underlying causes of these conditions.
Cosmetic dermatologists are often faced with patients presenting with melasma,
solar lentigos, postinflammatory hyperpigmentation, and circles under the eyes. It
is this {roup of conditions that is discussed here. Some treatment options are
discussed as well; however, depigmenting agents re discussed in greater detail in
Chap. 14.
Skin Color
color results from the incorporation of the melanin- f Staining melanosomes,
produced by the melanocytes, into icratinocytes in the epidermis, and their
ensuing ^ppadation. In darker-pigmented individuals, melanocytes jFOduce more
melanin, and the melanosomes are larger and heavily melanized, and undergo
degradation at a rate than in lighter skinned individuals.1 Melanin ^Produced by
the hydroxylation of tyrosine to 3,4- *tydroxyphenylalanine (DOPA) using the
enzyme tyrosi- ***< which subsequently oxidizes DOPA to dopaquinone.
leading to the formation of melanin (eumelanin and pheome- lanin)2 (Figure 10-
1).
After the melanin is made within the melanosomes, it then migrates into the
melanocytes dendrite tips using myosin V filaments3 and a dynein motor.4
Each melanocyte is in contact with several neighboring ker- atinocytes, forming
an epidermal melanin unit. The melanin in the melanocytes is then incorporated
into other keratinocytes of the epidermal melanin unit, or into the dermis by a
process that is still poorly understood. Several mechanisms have been proposed
for this transfer of melanin to the neighboring keratinocytes. The first involves
phagocytosis. Melanin is released into the dermis following damage to
melanocytes in the basal layer and is then phagocy- tized by melanophages.
Another proposed mechanism of melanin transfer is endocytosis. This process
involves the melanosomes being discharged directly into the intercellular spaces
followed by endocytosis. Others have postulated that direct inoculation or
injection of the melanin into the melanocytes occurs. The final hypothesis is that
the melanin transfer occurs by keratinocyte-melanocyte membrane fusion.5
Although the exact process of melanin transfer is poorly understood, new
discoveries are rapidly being made in this area. Recent studies have provided
some insight into how melanin is incorporated into keratinocytes. For example,
Seiberg et al.6 found that the protease-activated receptor 2 (PAR-2), expressed on
keratinocytes but not on melanocytes, is important in regulating the ingestion of
melanosomes by keratinocytes in culture. PAR-2 is a G-protein-coupled receptor
that is activated by a serine protease cleavage.' It is thought to be important in
hyperpigmentation disorders because it has been found that serine protease
inhibitors that interfere with PAR-2 activation induce depigmentation by affecting
melanosome transfer and distribution. In addition, activation of PAR-2 with
trypsin and other synthetic peptides has been shown to result in visible skin
darkening.8 Discoveries such as these may lead to new understanding of these
hard to treat pigmentary disorders.
Ultraviolet Light: and Skin Color
Ultraviolet (UV) irradiation is a major source of environmental damage to skin.
When exposed skin is subjected to LJV light, mclanogcncsis or tanning occurs
and represents the skins major defense against further UV damage. This
darkening occurs when the ultraviolet radiation provides a positive signal to the
exposed epidermal melanin units. The number of melanocytes that are actively
producing melanin increases. In addition, melasome transfer form the melanocytes
to the keratinocytes is enhanced.9 The resulting increase in melanin protects
against further UV damage by absorbing UV photons and UV-gencratcd free
radicals before they can react with DNA and other critical cellular components.
Recent research by Gilcrest et al.1 demonstrated that DNA damage or DNA
repair intermediates can stimulate melanogenesis in the absence of UV light. In
fact, small single-stranded DNA fragments such as thymidine dinucleotides
(pTpT) are able to stimulate tanning when applied topically to intact skin in the
absence of DNA damage." These discoveries may lead to more insight into the
cause of disorders of pigmentation, and may have utility in providing protection
from the damage caused by UV light. (Not to mention a possible cosmetic product
resulting in a safe tan.) Interestingly, it has been demonstrated that pTpT may
also induce other pholoprotcctivc responses such as enhanced DNA repair and
induction of tumor necrosis factor (TNF)-a through the induction and activation of
the p53 tumor suppressor and transcription factor.12
Melasma
Melasma, also known as chloasma or mask of pregnancy, refers to a very
common condition that is usually seen in women of childbearing age (Figure 10-
2). It is a chronic disorder that can be frustrating to patients and physicians alike
because it is very difficult to treat. Melasma presents as irregularly shaped, but
often distinctly defined, blotches of light- to dark-brown pigmentation. These
patches arc usually seen on the upper lip, nose, cheeks, chin, forehead, and.
sometimes, the neck. There arc three typical patterns of distribution; the most
common pattern is cemrofacial, involving the cheeks, forehead, upper lip, nose,
and chin.13 The malar pattern, which affects the nose and cheeks, and the
mandibular pattern are less common. Melasma is most commonly seen in areas
that receive sun exposure; however, it has been reported on the nipples and around
the external genitalia.14,15
Etiology
Melasma is a fairly typical physiological occurrence that is seen most often during
pregnancy or oral contraceptive use.
Melasma 6 5
Figure 10-2.
Patient with diffuse melasma. The patient has not improved despite multiple
therapies including depigmenting agents, chemical peels, and good sun
protection.
It can occur at any time during a womans reproductive years, and is more
common in women of darker skin types. Although there have been many
suggested causative factors, estrogen and ultraviolet light seem to be the biggest
culprits. It is so common in pregnancy that it has been given the nickname mask
of pregnancy. It is currently unknown how increased estrogen levels lead to
melasma; however, recent studies suggest that estradiols may play an important
role in the etiology. 17-/3-Estradiol, which is known to affect other cells of neural
crest origin, significantly increases the activity of tyrosinase when added to
melanocyte cultures.16 However, melasma also occurs in men, in about 10 percent
of cases, most often in men of Middle Eastern, Caribbean, or Asian descent. Solar
exposure is well known to exacerbate the condition and seems to be necessary for
development of this disorder.17-18 In fact, melasma has been reported to be less
noticeable in the winter months, when sun exposure is typically lower.19
The other proposed causes of melasma include genetic predisposition, nutritional
deficiency, and other hormones such as progesterone, although the exact etiology
remains vague.20-21 In addition, the antiepileps) drugs Hydantoin and Dilantin are
implicated in contributing to melasma in both women and men.22-23
Approximate!) one-third of cases in women, and most cases in men, are
idiopathic.24 Some authors have hypothesized an endocrine causal mechanism.25
but no such mechanism has been established.26 Although there have been a few
familial cases reported, the evidence that melasma can be inherited is thin.* Heat
may play a role in melasma as well. Many women develop melasma on the upper
lip after hot wax has been used as a hair removal method. Although this may
represent a coincidence, it is so commonly reported by patients that the author
believes that heat may play a role in melasma as it does in erythema ab igne.
(Erythema ab igne is a reticulated erythematous
hyperpigmented eruption that occurs after chronic exposure to heat.)
Authors have noted that melasma most often appears in young women who are
psing oral contraceptives.28,29 Melasma is also common among pregnant women,
and together these two conditionsuse of oral contraceptives and pregnancy
comprise the majority of melasma cases. Menopausal and premenstrual
presentations occasionally occur as well. Although estrogen is thought to play a
major role in the etiology of melasma, there is a low incidence of melasma cases
among postmenopausal women on estrogen replacement therapy.30 Although
melasma may diminish in the months following a patients pregnancy or after she
discontinues oral contraceptives, the condition often persists, taking up to five
years to resolve.31,32 The course of the condition varies significantly from patient
to patient and within individual women, from pregnancy to pregnancy.33 Increased
incidence of melasma also coincides with some ovarian disorders. Unfortunately,
once patients develop melasma, they have a high chance of experiencing a recur-
rence of this difficult disorder.
Histopathology
In epidermal melasma, which appears brown, the basal and suprabasal layers have
a higher-than-normal level of melanin, which can also be present throughout the
epidermis.34'35 With the dermal presentation, which appears blue- gray, melanin-
laden macrophagcs occur in a pcrivascular arrangement in the superficial and
middle level of the dermis. There are no known effective treatments for dermal
melasma. A mixed hypermelanosis, which appears brown- gray, can also occur.
Only the epidermal component can be treated.
Epidermal versus Dermal Disease
Because the epidermal component is amenable to treatment whereas the dermal
component is not, it is helpful to determine the extent of the dermal component in
order to predict accuratcly a patients treatment response and to provide the
patient with the proper expectations. It is helpful to use a Wood light to examine
the face at the initial visit. The epidermal component will appear darker under
Wood light examination, while the dermal component will be less visible.36 In
other words, if the lesions are more pronounced with a Wood light examination,
there is a better chance for clinical improvement. Wood lamp examination did not
help to predict the clinical response to peels in a study by Lawrence, however.37
The investigators felt that this occurred because there was such a high number of
patients with a mixed epidermal/dermal form of melasma. However, the
consensus remains that patients in whom epidermal melasma predominates may
respond better than those with a large dermal component. Therefore, the Wood
light exam
is still a useful adjunct to determine a patients prognosis the treatment of
melasma.
Treatment
The therapeutic objective is to retard the proliferation of melanocytes, inhibit the
formation of melanosomes, and pro. mote the degradation of melanosomes.38
Treatment option are discussed in Chap. 14, but must include a good high.
SPF sunscreen with UVA protection and sun avoidance. The sunscreen must be
worn 24 hours a day. Sun avoidance, UV^ screens for car and home windows, and
protective clothing, such as hats, are a great addition to a topical treatment re?,
men. Topical treatments may include hydroquinone 2 to4% low-potcncy steroids,
kojic acid, arbutin, azelaic acid, hv. droxy acids, and retinoids. Although tretinoin
0.1 % has been studied as a single agent in the treatment of melasma,3940 :he time
to improvement is lengthy (10 months in one studv). rherefore, most physicians
use a combination of topical Droducts. The Kligman formula is a mixture
consisting of 3.1% tretinoin, 5.0% hydroquinone, 0.1% dexamethasone, ind
hydrophilic ointment.41 It has been a very popular melasma treatment since its
introduction in 1975; however,, his formula is currently not commercially
available and must be formulated by a pharmacy.
Recent studies have shown that glycolic acid is also ben* y ificial in enhancing the
effectiveness of hydroquinone.42 The,
Regimen for Patients with Melasma Morning
1. Wash with an a-hydroxy acid-containing cleanser.
2. Apply a product with a combination of hydro- _ quinone and kojic acid.
3. Apply a UVA/UVB sunscreen.
4. Wear a hat and avoid sun when possible.
Evening
1. Wash with an a-hydroxyacid-conta;ning cleanser.
2. Apply a retino;d such as Retin-A. Renova,
Differin, Taza-ac, or Alustra.
Undergo an in-ofHce peel every two weeks (i.e., Jessners,;|| glycolic, or salicylic
acid). Slowly increase peel strength Jl as tolerated.
NOTE: Some patients develop exogenous ochronosis, or in- 'fl creased
pigmentation, on exposure to hydroquinone. A good ^ history should be taken,
and if the patient is sensitive to hy*^E droquinone, it should be avoided. Azelaic
acid (Azelex) is an- M other option that is useful in all patients, but especially in
those .* patients who cannot tolerate hydroquinone.
Solar Lentigos 67

Figure W--i.
A patient *ith melasma of the upper lip and cheeks.
lion of glycolic acid facilitates penetration of both agents* promoting
efficacy. Glycolic acid can be used in a ^nical peel formulation or as an additive
to home prod- ycts. Glycolic acid peels and/or Jessners peels can be used n
combination with topical agents^to hasten the resolution 0f melasma (see Chap.
20). Lawrence et al. found that Jessys solution and 70% glycolic acid (combined
with uttinoin and hydroquinone between peels) worked equally well in the
treatment of melasma.43
The addition of kojic acid may also improve the efficacy of topical agents
according to other recent studies. Research performed in Singapore followed 40
Chinese women treated with 2% kojic acid in a gel containing 10% glycolic acid
and 2h hydroquinone on one half of the face.44 The other half was treated with
the same application but without kojic acid. The patients were observed for 12
weeks. All patients showed improvement in melasma on both sides of the face;
however, the side treated with the combination containing kojic acid showed more
improvement More than half of the melasma cleared in 24 of 40 (60%) patients
receiving kojic acid as compared to 19 of 40 (47.5%) patients receiving the gel
without kojic acid.
Because there are so many treatment options and compliance is a vital part of
the treatment of this condition, the regimen should be easy for the patient to
understand. Many companies, such as Biomedic and Obagi, package products in
an easy-to-understand treatment regimen. Although these products contain similar
ingredients to those available with a prescription, the bottles are often numbered
Step 1, Step 2, and so on, which makes it much easier for the patient to understand
which creams to use and when to use them [Figure 10-3).
~{~ instructions of how and when to use prescription
m
prescription products, the numbering system on the bottles
* tcsJ for patients to be compliant. Unfortunately, this vtry
expensive. The same results can be achieved by ivirg
10-3.
S/sten-. Although the ingredients in this system are also
Patient education is one of the most important aspects in the treatment of
melasma. Most patients do not realize the important role of ultraviolet radiation in
this condition and they do not realize that UVA rays can penetrate glass. Patients
should be instructed to wear during all daylight hours a UVA and UVB sunscreen
of the highest SPF that they can tolerate. Patients should also understand that no
sunscreen offers complete protection; therefore, sun avoidance should also be
practiced. Because patients may have difficulty seeing the improvement in their
skin, serial photography with a regular camera and a UV camera, can be used to
document treatment response45 (Figure 10-4).
Solar Lentigos
As many as 90 percent of patients age 65 years or older have one or more solar
lentigos.40 As the name suggests, the sun is the culprit here, with both acute and
chronic exposure linked to engendering these macular brown lesions usually 1 cm
in diameter. The face and backs of hands are the typical areas affected. Because
these lesions are seldom seen among patients under 50, they are also called senile
lentigos. The sun, rather than age, is the causative factor, however. These lesions
do not occur on sun-protected skin, even in the elderly (Figure 10-5). Solar
lentigos, freckles (ephelides). and lentigos simplex are difficult to distinguish
from each other clinically. Taken together, these types of

Figure TO-S.
Solar lentigos occur only in sun-exposed skin. Because the flexor surface of the
forearm receives much less sun exposure, it demonstrates fewer solar lentigos
than does the extensor surface of the forearm.
lesions constitute a significant risk factor for melanoma47 and basal cell
carcinoma.48
Histopathology
Solar lentigos demonstrate elongated rete ridges that contain deeply pigmented
basaloid cells intermingled with melanocytes. Also, they have an elevated number
of melanocytes, which have an increased capacity for melanin production.49 Solar
lentigos can be distinguished from freckles histologically because freckles do not
have elongated rete ridges and have a normal or lower number of melanocytes
(Figure 10-6).
Prevention of solar lentigos is best achieved through use of sunscreens and sun
avoidance. A study published in JAMA demonstrated that the use of sunscreen
helped di-

10-6.
Hematoxylin and eosin (H<&E) stain of a solar lentigo. (Photo courtesy of
George loannides, MD.)

Figure 10-5.
Solar lentigos occur only in sun-exposed skin. Because the flexor surface of the
forearm receives much less sun exposure, it demonstrates fewer solar lentigos
than does the extensor surface of the forearm.
lesions constitute a significant risk factor for melanoma47 and basal cell
carcinoma.48
Histopathology
Solar lentigos demonstrate elongated rete ridges that contain deeply pigmented
basaloid cells intermingled with melanocytes. Also, they have an elevated number
of melanocytes, which have an increased capacity for melanin production.49 Solar
lentigos can be distinguished from freckles histologically because freckles do not
have elongated rete ridges and have a normal or lower number of melanocytes
(Figure 0-6).
Prevention of solar lentigos is best achieved through use of sunscreens and sun
avoidance. A study published in JAMA demonstrated that the use of sunscreen
helped di-

f i^um 10-6.
Hematoxylin and eosin (H&E) stain of a solar lentigo. (Photo courtesy of George
loannides, MD.)
m
SO
minish the occurrcncc of nevi in white children. Because increased numbers of
these nevi are associated with an ele. vated risk of melanoma, the importance of
preventing the onset of such lesions cannot be overstated.
Treatment
Solar lentigos can be treated with a variety of methods depending on convenience
for the patient. For example, some patients may want to treat with slower methods
that require no down time; other patients may want to have the lesions removed in
as few office visits as possible and dont mind the down time. All patients should
be treated with a home regimen of sunscreen and a combination of topical
retinoids, topical bleaching agents, and hydroxy acids. For those who want faster
and more visible results TCA peels, lasers (Q- switch ruby, Alexandrite, and
Nd:Yag), local dermabrasion, and cryotherapy can be used. Several studies have
compared the efficacy of these various treatments. An ingenious method
developed by Hexsel uses a tiny dermabrasion instrument to remove the solar
lentigos.51 She treated 10 female patients with solar lentigos on the back of the
hands with either localized dermabrasion or cryotherapy. More than 50 percent of
the patients treated with cryotherapy continued to have hypochromia in the treated
areas six months after treatment, as compared with 11 percent of the patients
treated with dermabrasion. The percentage of recurrence of solar lentigos was the
same with both treatments (55.55 percent). Laser therapy is also effective in
treating solar lentigos. One study examining the efficacy of the Q-switched ruby
laser in the treatment of solar lentigos demonstrated a response rate of 70 percent
after one or two treatments.52 Although lasers are very effective for these lesions,
patients should be warned that treated areas will have a scab for approximately 7
to 10 days. Patients are usually not pleased at the prospect of attending social
function? with scabs all over their hands and arms. For patients with active social
lives, a few lesions per visit can be treated to avoid the chickenpox look.
It is important to remember that patients with multiple solar lentigos are at an
increased risk for skin cancer. There is no evidence or reason to believe that
successful treatment of these lesions leads to a lower melanoma risk. Therefore,
patients with significant numbers of solar lentigos, treated or untreated, should
undergo routine skin cancer exams.
Tannino-oeII" Lentigities
The development of unusual melanocytic lesions after exposure to UVA tanning
beds has been reponed. Clinically, these lesions appear similar to the lentigines
that occur after psoralen photochemotherapy.5' Histological examination of these
lentigos revealed melanocytic hyperplasia and cy-
l0l0gic atypia.'4 Therefore, patients with these lesions may at an increased risk of
skin cancer. These patients should cautioned about the hazards of tanning-bed use
and should have yearly skin exams.
Postinflammatory Hyperpigmen tation
postinflammatory hyperpigmentation, also known as post- inflammatory pigment
alteration (PIPA), is caused by a variety of skin disorders. Occasionally, therapies
for skin disease can cause or exacerbate dyschromia. Although postinflammatory
hyperpigmentation appears most frequently among patients with darker skin
types, it can afflict people of any skin type.55-57 Minor conditions such as acne,
eczema, and allergic reactions can lead to PIPA. Also, more serious cutaneous
events, such as burns, surgeries, and trauma, or treatments, such as chemical peels
and laser resurfacing, can precipitate it. Unfortunately, this phenomenon tends to
recur in susceptible individuals.58
PIPA presents as irregular, darkly pigmented spots arising in areas of previous
inflammation.59 Postinflammatory hyperpigmentation can appear in any part of
the skin, but is a particularly significant source of distress to a patient when it
occurs in the face. In fact, PIPA is one of the most common conditions
responsible for spurring patients to visit a dermatologist.
Etiology
Postinflammatory hyperpigmentation is a consequence of increased melanin
synthesis in response to a cutaneous insult. It can be diffuse or localized, and its
distribution depends on the location of the original injury.
Histopathology
PIPA is characterized by numerous melanophages in the superficial dermis. An
inllltrate of lymphohistiocytes may he seen around superficial blood vessels and in
dermal papillae.60
Treatment
PIPA is difficult to treat because it occurs in individuals sus- ccptiblc to
hyperpigmentation following inflammation. Finder inflammation, as induced by
peels or lasers, would worsen the process. Consequently, only nonirritating topical
products, such as hydroquinone, kojic acid, and retinoids, potentially useful to
treat this condition. These agents ^ve minimal efficacy, however. The best
treatment approach is sun avoidance, sunscreen use. and patience bemuse these
lesions lend to improve with time.
Under-Eye Circles
Under-eye circles are a common complaint by both men and women. The cause of
these dark circles under the eyes is poorly understood. Many believe that the thin
skin in this area allows the blood vessels to become more visible. Any
inflammation or vasodilation in this area may manifest as darkening. However,
there also.seems to be a pigmentary component that is poorly understood. There
are many anecdotal reports of using pigmented lesion lasers such as the Ruby or
NdrYag to treat these lesions; however, there is no published data evaluating these
therapies. A study by Elson61 that evaluated the use of vitamin K (phytonadione)
combined with retinol 0.15% for the treatment of periorbital hyperpigmentation
demonstrated that this preparation was effective in improving under-eye circle in
93 percent of the patients studied.
Many cosmetic companies claim that their creams erase dark circles. These
creams usually contain depigmenting agents; however, it is unproven whether this
condition is caused by excessive melanin production. In fact, some physicians
have postulated that the circles are caused by deposition of hemosiderin.
Unfortunately, there is no published research in this area to explain the cause and
the best treatment of these under-eye circles. For now, it seems certain that the
best treatment options at patients disposal are sunscreen and increased rest. Of
course, good genes might make this condition less likely, but this is obviously not
under patient or physician control. There are currently no available and effective
treatments.
Camouflage Cosmetics
In recalcitrant disorders such as melasma, camouflage cosmetics can be used to
give the patient a more natural appearance during the treatment process. These
products are opaque and do not allow the underlying skin tones to be seen. The
product is usually a thick cream that can be made to match a normal skin tone,
thus masking the underlying abnormality. Some companies have developed
advanced techniques using a spectrophotometer to measure skin color. The data
from the spectrophotometer is used to create a pigment-rich foundation that
exactly matches the patient's skin lone. Because there is such a wide variety of
skin tones, these products provide the best solution for patients v.ith hard to match
skin tones. Another option is to use a color that is complementary to the unwanted
color. An example of this is using green to cover red discolorations, or purple to
cover yellow discolorations. Yellov. and while camouflage products are the most
effective in treating melasma and other brown pigmentation disorders. Patients
then apply their normal facial foundation on lop of the color camouflage in order
to uchicvc the most natural look. There arc many brands of cover cosmetics
available, including CoverBlend, Cover- mark, Christian Dior, Dermablend, Hard
Candy, Joe Blasko, MAC, and Neutrogena.,
Summary
All skin types are susceptible to pigmentation disorders. Such alterations can be
particularly prominent in people with dark skin tones. Therapy is difficult and
occasionally frustrating for both the patient and the dermatologist as it requires
protracted topical application of agents, sun avoidance, and, often, in-office
chemical peels. Unfortunately, there is no panacca to treat these intractable
disorders and attempts at resolving the particular condition often entail trying
many different therapies with varying degrees of success.
References
5. Szabo G, Gerald AB, Pathak MA, et at: Racial differences in the fate cf
melanosomes in human epidermis. Nature 222:1081, 1969.
6. Freedberg IM. Eisen AZ, Wolff K, et at, eds: Fitzpatricks Dermatology in
General Medicinc. 5th ed. New York. McGraw-Hill, 1999, p. 996.
7. Wei Q, Wu X. Hammer JA 3rd: The predominant defect in dilute melanocytes
is in melanosomc distribution and not cell shape, supporting a role for myosin
V in melanosome transport. J Muscle Res Cell Motil 18:517, 1997.
8. Ogawa K, Hosoya H, Yokota E, et at: Melanoma dynein: Evidence that dynein
is a general motor for microtubule- associated cell motilities. Eur J Cell Biol
43:3, 1987.
9. Seiberg M, Paine C, Shadow E, et at: inhibition of melanosome transfer results
in skin lightening. J Invest Dermatol 115:162,2000.
10. Seiberg M, Paine C, Shadow E, et at: Inhibition of melanosome transfer
results in skin lightening. J Invest Dermatol 115:162,2000.
11. Nystedt S, Emilsson K, Larsson AK. Strombeck B,
Sundelin J: Molecular cloning and functional expression of the gene encoding the
human proteinase-activated receptor
3. Eur J Biochem 232:84, 1995.
12. Seiberg M. Paine C. Shadow E. et at: The protease- activated receptor-2
regulates pigmentation via keratinocyte-melanocyte interactions. Exp Cell Res
254:25, 2000.
13. Hermanns J. Petit L, Martalo O, Pierard-Franchimont C. Cauwenbergh G.
Pierard G: Unraveling the patterns of subelinical pheomelanin-cnriched facial
hyperpigmcntation: lilTcci of depigmenting agents. Dermatology 201:1 IX.
2000.
14. Goukassian D. Eller M. Yaar M. Gilchrest B: Thymidine dinucleotide mimics
the effect of solar simulated irradiation on p53 and p53-regulated proteins. J
Invest Dermatol I 12:25. 1999.
15. Gilchrest BA. Eller MS: DNA photodamage stimulates mclanogenesis and
other photoprotective responses. J Inv< Dermatol 4(1 ):35, 1999.
16. Hadshiew IM, Eller MS, Gasparro FP, Gilchrest BA: Stimulation of
mclanogenesis by DNA oligonucleotides: Effect of size, sequence and 5'
phosphorylation. J Derniai Sci 25(2): 127, 2001.
17. Mandry Pagan R, Sanchez JL: Mandibular melasma. P R Health Sci J 19:231,
2000.
18. Baran R. Maibach HI, eds: Textbook of Cosmetic Dermatology, 2nd ed.
London. Dunitz Martin, 1998. p. 396.
19. Arnold H, Odom RB, James WD, eds: Andrews Disease of the Skin:
Clinical Dermatology, 8th ed. Philadelphia, WB Saunders. 1990. p. 991.
20. McLeod SD, Ranson M, Mason RS: Effects of estrogens on human
melanocytes in vitro. J Steroid Biochem Mol Biol 9(l):9, 1994.
21. Freedberg IM, Eisen AZ, Wolff K, et at, eds: Fitzpatricks Dermatology in
General Medicine, 5th ed. New York, McGraw-Hill, 1999, p. 996.
22. Sanchez NP, Pathak MA, Sato S, et at: Melasma: A clinical, light microscopic,
ultrastructural, and immunofluorescence study. J Am Acad Dermatol 4:698,
1981.
23. Freedberg IM, Eisen AZ, Wolff K, et al, eds: Fitzpatrick's Dermatology in
General Medicinc, 5th ed. New York, McGraw-Hill, 1999, p. 996.
24. Arnold H, Odom RB, James WD, eds: Andrews Diseases of the Skin:
Clinical Dermatology, 8th ed. Philadelphia, WB Saunders, 1990, p. 991-994.
25. Baran R, Maibach HI, eds: Textbook of Cosmetic Dermatology, 2nd ed.
London. Dunitz Martin, 199S. p. 396.
26. Champion RH, Burton JL, Ebiing FJG, eds: Rook. Wilkinson, Ebiing:
Textbook of Dermatology, 5th ed. London. Blackwell Science, 1992, p. 1596.
27. Arnold H, Odom RB, James WD, eds: Andrews Disease; of the Skin: Clinical
Dermatology, 8th ed. Philadelphia, WB Saunders, 1990, p. 991.
28. Ibid.
29. Arnold H, Odom RB, James WD, eds: Andrews' Disease.* of the Skin:
Clinical Dermatology, 8th ed. Philadelphia, WB Saunders, 1990, p. 991.
30. Champion RH, Burton JL. Eriing FJG. eds: Rook. Wilkinson, Ebiing:
Textbook of Dermatology, 5th ec. London. Blackwell Science. 1992, p. 1596.
31. Ihid.
32. Baran R. Maibach HI, eds: Textbook of Cosmetic Dermatology, 2nd ed.
Londor. Dunitz Martin, 1995. p. 396.
33. Arnold II. Odom RB. JaiiK> ^ I), eds: Andrews' D.'Case: of the Skin: Clinical
Dermatology. 8th ed. Philadeirhia. WB Saunders, 1990, p. 991.
34. Freedberg IM. Eisen AZ, Wolff K. et al, eds: Fitzpatrick: Dermatology in
General Medicine. 5th ed. New York. McGraw-Hill. 1999. p. 996.
(31) Champion RH, Burton JL, Ebling FJG, oils: Rook, Wilkinson, Ebling:
Textbook of Dermatology, 5th cd. London, Blackwell Science, 1992, p. 1596.
(32) Arnold H. Odom RB. Jamcjj WD, eds: Andrews' Diseases of the Skin:
Clinical Dermatology, 8th ed. Philadelphia,
WB Saunders, 1990, p. 991.
(33) Freedberg IM, Eisen AZ, Wolff K, et al, eds: Fitzpatricks Dermatology in
General Medicine, 5th ed. New York, McGraw-Hill, 1999, p. 996.
(34) Baran R, Maibach HI, eds: Textbook of Cosmetic Dermatology, 2nd ed.
London, Dunitz Martin, 1998, p. 396.
(35) Freedberg IM, Eisen AZ, Wolff K, et al, eds: Fitzpatricks Dermatology in
General Medicine, 5th ed. New York, McGraw-Hill, 1999, p. 996.
(36) Gilchrest BA, Fitzpatrick TB, Anderson RR, et al: Localization of melanin
pigmentation in the skin with Woods lamp. Br J Dermatol 96:245, 1977.
(37) Lawrence N, Cox SE, Brody HJ: Treatment of melasma with Jessners
 solution versus glycolic acid: A comparison of clinical efficacy and evaluation
of the predictive ability of Woods light examination. J Am Acad Dermatol
36:589, 1997.
(38) Pandya AG, Guevara 1L: Disorders of hyperpigmentation. Dermatol Clin
18:91, 2000.
(39) Griffiths CE, Finkel LJ, Ditre CM, et al: Topical tretinoin (retinoic acid)
improves melasma: A vehicle-controlled, clinical trial. Br J Dermatol 129:415,
1993.
(40) Kimbrough-Green CK, Griffiths CE, Finkel LJ, et al: Topical retinoic acid
(tretinoin) for melasma in black patients: A vehicle-controlled clinical trial.
Arch Dermatol 130:727, 1994.
(41) Kligman AM. Willis I: A new formula for depigmenting human skin. Arch
Dermatol I 11:40, 1975.
(42) Lim JT, Tham SN: Glycolic acid peels in the treatment of melasma among
Asian women. Dermatol Surg 23:177,
1997.
(43) Lawrence N, Cox SE, Brody HJ: Treatment of melasma with Jessners
solution versus glycolic acid: A comparison of clinical efficacy and evaluation
of the predictive ability of Woods light examination. J Am Acad Derma:ol
36:589, 1997.
(44) Lim JT: Treatment of melasma using kojic acid in a gel containing
hydroquinone and glycolic acid. Dermatol Surg 25:282. 1999.
(45) Fulton JE Jr: Utilizing the ultraviolet (UV detect; camera to enhance the
appearance of photodamage and other skin conditions. Dermatol Surg 23:163.
1997.
(46) Hodgson C: Senile lentigo. Arch Dermatol 87:197. 1963.
(47) Bliss JM. Ford D, S word low AJ, el at: Risk of cutaneous melanoma
associated with pigmentation characteristics and freckling: Systematic
overview of 10 case-control studies. The International Melanoma Analysis
Group (IMAGK). Ini J Cancer 62:367, 1995.
(48) Naldi L, DiLandro A. DAvanzo B, et al: Hosl-related and environmental risk
factors for cutaneous basal cell carcinoma: Evidence from an Italian casc-
conlrol study. J Am Acad Dermatol 42:446, 2000.
(49) Hodgson C: Senile lentigo. Arch Dermatol 87:197, 1963.
(50) Gallagher RP, Rivers JK, Lee TK, et a!: Broad-spectrum sunscreen use and
the development of new nevi in white children: A randomized controlled trial.
JAMA 283:2955. 2000.
(51) 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 26:457, 2000.
(52) Shimbashi T, Kamide R, Hashimoto T: Long-term follow- up in treatment of
solar lentigo and cafe-au-lait macules with Q-switched ruby laser. Aesthetic
Plast Surg 21:445. 1997.
(53) Salisbury JR, Williams H, du Vivier AW: Tanning-bed lentigines:
Ultrastructural and histopathologic features. J Am Acad Dermatol 21(4 Pt
l):689, 1989.
(54) Roth DE, Hodge SJ, Callen JP: Possible ultraviolet A-induced lentigines: A
side effect of chronic tanning salon usage. J Am Acad Dermatol 20(5 Pt
2):950, 1989.
(55) Burns RL. Prevost-Blank PL, Lawry MA, et al: Glycolic acid peels for
postinflammatory hyperpigmentation in black patients. Dermatol Surg 23:171,
1997.
(56) Grimes PE, Stockton T: Pigmentary disorders in blacks. Dermatol Clin 6:271,
1988.
(57) Ruiz-Maldonado R, Orozco-Covarrubias ML: Postinflammatory
hypopigmentation and hyperpigmentation. Semin Cutan Med Surg 16:36,
1997.
(58) Fairley JA: Tretinoin (retinoic acid) revisited. N Engl J Med 328:1486, 1993.
(59) Bulengo-Ransby SM. Griffiths CE, Kimbrough-Green CK, et al: Topical
tretinoin (retinoic acid) therapy for hyperpigmenled lesions caused by
inflammation of the skin in black patients. N Engl J Med 328:1438, 1993.
(60) Spielvogel R, Kantor G: Pigmentary disorders of the skin. In: Elenilsas R, ed:
Levers Histopathology of the Skin,
Sth ed. Philadelphia. Lippincott Williams & Wilkins, 1997. p. 618.
(61) Elson M, NacHT S: Treatment of periorbital hyperpigmentation with topical
vitamin KAitamin A. Cosmetic Dermatol 12( 12):32, 1999.