Photoaging and Pigmentary Changes of the Skin 3 Susan C

Chapter 3 Photoaging and Pigmentary Changes of the Skin 3 Susan C. Taylor

Contents Core Messages 3.1 Introduction ...... 29 í Several mechanisms and mediators 3.2 Mechanisms of Aging ...... 31 appear to control human aging, including longevity genes, cell death me- 3.3 Clinical Characteristics of Photoaging diated by telomere shorting, and free and Pigmentary Changes ...... 33 3.3.1 Asian Skin ...... 34 radical activation. 3.3.2 African American Skin ...... 36 3.3.3 Caucasian Skin ...... 38 í Clinical characteristics such as pigmentary changes and photoaging 3.4 Histology of Photoaged Skin . . . . . 41 overshadow those of intrinsic aging. 3.4.1 The Pigmentary System Pigmentary changes are major compo- in Photoaged Skin ...... 43 nents of photoaging in the major skin 3.5 Overview of Prevention of Photoaging types, including Asian, African Ameri- and Pigmentary Changes of the Skin .44 can, and Caucasian. 3.6 Overview of Treatment of Photoaging and Pigmentary Changes of the Skin .45 í Intrinsic aging is marked by atrophy 3.7 Summary ...... 48 of the epidermis and dermis whereas References ...... 49 photoaging is marked by dysplasia of epidermal cells, melanocyte heterogeneity, and elastosis of the dermis.

í Features of photoaging, including pig- 3.1 Introduction mentary changes, may be prevented by limiting ultraviolet (UV) light expo- The inevitable process of aging begins at the sure. time of birth. With maturity, the features of intrinsic or chronological aging become appar- í Use of sunscreen to block both UVA ent. The cutaneous manifestations of chrono- and UVB light is an important preven- logical aging are manifold and include a tative measure. smooth, pale appearance of the skin with fine wrinkling and loss of hydration [1]. The charac- í Antioxidants most likely play a role in teristics of intrinsic aging are often overshad- the prevention of photoaging. owed by those of photoaging. Photoaging, aging of the skin induced by repeated exposures to ultraviolet (UV) light, leads to dramatic changes in the skin. These differences are highlighted by twin studies performed by New York City plastic surgeon Dr. Darrick E. Antell in which one twin with a significant sun exposure 30 Susan C.Taylor

history displayed dramatic wrinkling com- Asians, African Americans, and Caucasians. pared with her sun-protected twin (Fig. 3.1a,b). Epidermal melanin content and melanosomal Clinical characteristics of photoaging include distribution mediates the damaging effect of fine and coarse wrinkling, roughness, dryness, UV light and accounts for much of the differ- telangiectasia, cancerous lesions, precancerous ence. The mean protective factor for UVA and lesions, and pigmentary alterations. Pigmen- UVB (which is equivalent to endogenous sun 3 tary alterations are a major component of pho- protection factor) differs quite substantially toaged skin and may be observed all skin types between whites and blacks [3]. Additionally, in- [2]. Pigmentary alterations associated with dividual sun exposure habits strongly influence photoaged skin are of several varieties, includ- the degree of photodamage, with those individ- ing hypermelanosis as well as hypomelanosis. uals with greater sun exposure experiencing Mottled hyperpigmentation, ephelides, lenti- greater photodamage. Racial and ethnic vari- gines, and pigmented seborrheic keratoses are ability in photoaging is noted in relation to the the primary lesions of hypermelanosis. Guttate degree of wrinkling of the skin as well as with hypomelanosis, presenting as white spots, is the the type of pigmentary lesions that develop. primary manifestation of hypomelanosis asso- Both intrinsic aging and photoaging are ciated with aged skin. complex processes. Histological characteristics Intrinsic aging occurs universally in individ- of intrinsic aging and photoaging have been uals of all racial and ethnic groups and with all studied via electron and light microscopy. Fur- skin types. In contrast, there is variability in the thermore, an understanding of the underlying severity and manifestations of photoaging in mechanisms responsible for aging is being

Figs. 3.1a,b. The manifestations of photoaging after repeated exposures to ultraviolet light are highlighted by twin studies performed by New York City plastic surgeon Dr. Darrick E. Antell in which one twin with a significant sun- exposure history displays dramatic wrinkling (a) compared with her sun-protected twin (b) Photoaging and Pigmentary Changes of the Skin Chapter 3 31 achieved. This includes genetic as well as envi- to stresses such as ultraviolet radiation, oxida- ronmental factors. Advances in both invasive tive damage, starvation, and temperature ex- and noninvasive therapeutic modalities for the tremes.There are conceivably many ways to im- treatment of photoaging have lead to the bur- pact these genetic processes and improve lon- geoning field of cosmetic dermatology. These gevity, such as caloric restriction, which may aspects will be discussed in this chapter, with potentially affect metabolic control and stress. an emphasis on the pigmentary changes of Many human homologs of the longevity genes photoaging. found in lower organisms have been identified and are currently being studied [5]. It is pro- posed that manipulation of these genes might 3.2 Mechanisms of Aging improve human longevity. The fact that genes play a crucial role in ag- In the past decade, scientific research has made ing is supported by genetic disorders in which astounding progress in elucidating the mecha- the aging process is greatly altered, such as in nism of aging of the human body, including the Werner’s syndrome. Werner’s syndrome, a dis- integument.As one might expect,aging appears order of premature aging, is characterized by to be due to a composite of genetic as well as many features, including an aged appearance, environmental factors. There appear to be sev- premature canities, alopecia, skin atrophy, cata- eral mechanisms and mediators that control racts, arteriosclerosis, and death before age 50. the multiple components of the human aging Evaluation of individuals with this syndrome process. For example, in several lower species, has provided insight into one possible genetic the genes controlling longevity have been suc- mechanism of aging. The Werner’s syndrome cessfully identified; corresponding genes are gene, which was cloned by Yu, has been identi- now being investigated in humans. Derange- fied as a DNA helicase [6]. Defective DNA me- ments in the genes that control premature ag- tabolism as a result of the Werner’s syndrome ing syndromes have been identified and pro- mutation is felt to be responsible for premature vide insight into the mechanism of aging.Chro- aging in these individuals. In progeria, another mosomal structures responsible for cell senes- genetic disorder of accelerated aging, a misreg- cence are known to play a crucial role in both ulation of mitosis has been identified as the intrinsic and photoaging. Furthermore, the role mechanism of premature aging [7].An analysis of free radicals in the aging process has been of fibroblast mRNA levels in progeria patients long recognized. Finally, the likely molecular revealed misregulation of structural, signaling, mechanism whereby UV light produces cellular and metabolic genes. Thus, several different damage leading to photoaging has been eluci- genes may be responsible for various aspects of dated. Each of these components, as outlined aging. below, will lead to a more complete under- Much attention has been given to genetically standing of the complex process of aging in hu- programmed cell death as the final common mans. pathway to aging. Cellular senescence, the in- Although a gene that controls the overall ag- ability of cells to divide indefinitely (cell death), ing process has not been identified in humans, occurs as a result of intrinsic aging as well as in organisms such as fungi,yeast,and fruit flies, photoaging. Cell senescence is controlled by 35 genes that determine life span have been telomeres. Telomeres are the repeating DNA cloned [4]. These genes are responsible for base sequences thymine-thymine-adenine- many different functions, suggesting that there guanine-guanine-guanine (TTAGGG) at the are multiple mechanisms of aging. In the lower ends of chromosomes [8]. They are thousands organisms studied, Jazwinski identified four of base pairs long and protect the ends of each principle processes responsible for aging, chromosome from damage. Shortening of the which include: metabolic control, resistance to telomere has been demonstrated in older stress, gene dysregulation, and genetic stability. adults, compared with younger individuals, and Some of the longevity genes identified respond in individuals with premature aging as in 32 Susan C.Taylor

Werner’s syndrome, thus supporting the im- proteins, which leads to damage of those com- portance of telomeres in aging [9, 10]. With ponents. The damage done by free radicals con- each round of cell division, telomeres become tributes to aging. Both intrinsic and extrinsic shorter and shorter until a point is reached aging generate free radicals through either when the cell is no longer able to divide and cell internal oxidative metabolism or through ex- death occurs. There is a folded structure at the ternal environmental factors, including pollu- 3 very end of the telomere that consists of an ar- tion, cigarette smoking, and UV radiation [19]. ray of 150–200 single-stranded bases referred A common pathway involving telomeres links to as the 3′ overhang [11]. The 3′ overhang is free radicals to aging. Free radicals target the configured in a folded loop that serves a protec- guanine residues that make up 50% of the telo- tive function [12]. As the chromosome repli- mere overhang structure [20]. cates, a critical point is reached when the over- The likely molecular mechanism explaining hang is exposed and digested [13]. Cell signal- photoaging was elucidated by Fisher [21]. The ing occurs (by the ataxia telangiectasia mutated basic tenant is that in photoaging,UV light gen- kinase protein and the p53 tumor suppressor erates free HOs, which stimulate matrix metal- protein) causing senescence of cells, such as fi- loproteinases (MMP) that then degrade extra- broblasts and apoptosis of lymphocytes [14]. In cellular matrix components. More specifically, addition to repeated replication, as occurs in cell surface receptors, including epidermal intrinsic aging producing telomere shortening growth factor receptor and cytokine receptor, and disruption, acute DNA damage as occurs in on keratinocytes and fibroblasts are activated photoaging also leads to activation of the same by UV light. Three mitogen-activated protein mediators, telomere shortening, and cell senes- kinase (MAP) pathways are then activated: ex- cence. Acceleration of aging occurs with UV tracellular signal-regulated kinase (ERK), cJun damage that, in addition to shortening and dis- amino-terminal kinase (JNK), and p38. These rupting telomeres, causes increased cell divi- pathways converge in the cell nucleus, and two sion to repair DNA thus leading to even further transcription factor components, cFos and shortening of telomeres. Telomerase, a ribonu- cJun, combine to form activator complex 1 (AP- cleoprotein identified in tumor cells makes tel- 1). AP-1 then simulates the transcription of omeric sequences to replace shortened telo- MMP genes to produce collagenase, 92-kd ge- meres [15]. Bodnar demonstrated an extension latinase, and stromelysin-1. These enzymes de- of life span by the introduction of telomerase grade collagen, elastin, and other extracellular into retinal epithelial cells and fibroblasts [16]. matrix components. With repeated UV expo- In an experimental model utilizing DNA oligo- sure, more dermal damage occurs that cannot nucleotides, which mimic the telomere 3’ over- be fully repaired, leading over time to photo- hang, Gilchrest’s group demonstrated that aged skin. treatment with oligonucleotides may mimic In his elegant series of experiments, Fisher telomere disruption signals without affecting irradiated white skin with UV lights and then the cell’s own DNA and thus enhance the DNA evaluated it by a variety of techniques [21]. A repair process [17]. single exposure to UV irradiation increased the Although the free radical theory of aging has expression of the three MMPs previously dis- received much attention recently with the in- cussed compared with nonirradiated skin, creasing popularity and commercialization of which did not. Degradation of type I collagen antioxidant products, it is a theory that dates fibrils was increased by 58% in the irradiated back over 40 years [18]. The theory is that aging skin compared with nonirradiated skin. UV ir- is caused by free radicals or reactive oxygen radiation also induced tissue inhibitor of ma- species, which are molecules with an unpaired trix metalloproteinases-1, which partially in- electron. Free radicals that include singlet oxy- hibited MMPs. Of note, pretreatment of skin 1 – gen ( O2), superoxide (O2 ), hydrogen peroxide with tretinoin inhibited the induction and ac-

(H2O2), and hydroxyl radical (HO) strongly at- tivity of MMPs by 70–80% in connective tissue tract electrons from DNA, cell membranes, and as well as the outer layers of irradiated skin. Photoaging and Pigmentary Changes of the Skin Chapter 3 33

Kang recently demonstrated that the genera- prominent thinning after the eighth decade [23, tion of free radicals by UV light was impaired 24]. Additionally, melanocytes also decrease by the antioxidant genistein and the antioxi- during adulthood, with an estimated decrease dant precursors n-acetyl cysteine [22]. of 10% per decade [25]. As expected, pigmentary changes are not a prominent feature of intrinsically aged skin compared with photoaged skin (Fig. 3.2). Environmental factors that con- 3.3 Clinical Characteristics tribute to aging, such as pollution and smok- of Photoaging ing, produce marked wrinkling of the skin but and Pigmentary Changes not pigmentary abnormalities. There are several different manifestations of pigmentary alter- The clinical characteristics of photoaged skin ations associated with photoaged skin. These are more pronounced compared with those ob- include mottled hyperpigmentation, solar len- served in intrinsic aging (Table 3.1). It is these tigines, diffuse hyperpigmentation, pigmented changes that are of cosmetic concern to many seborrheic keratoses, and guttate hypopigmen- individuals as they overshadow those associat- tation. Some manifestations of photoaging are ed with intrinsic aging. In intrinsic aging, the more prominently displayed in certain racial skin has a pale appearance with fine wrinkling. groups compared with others. These differenc- It has been demonstrated that the dermis thins es will be discussed below and are highlighted by 20% with intrinsic aging, with the most in Table 3.2.

Table 3.1. Clinical characteristics of intrinsic aging and photoaging

Clinical characteristic Intrinsic aging Photoaging

Pigmentation Pale, white, hypopigmentation Mottled, confluent, and focal hyperpigmentation Wrinkling Fine lines Deep furrows Hydration Dry and flakey Dry and rough Growths Benign Cancerous and benign

Fig. 3.2. Pigmentary changes are not a prominent feature of intrinsically aged skin as seen on the sun-protected flexor arm compared with the pigmentation displayed on the sun exposed extensor arm of the same woman 34 Susan C.Taylor

Table 3.2. Pigmentary characteristics of photoaging in Asian, African American and Caucasian skin

Clinical Feature Asian African American Caucasian

Ephelides + – ++ Lentigines ++ – ++ 3 Mottled hyperpigmentation + + ++ Seborrheic keratoses ++ + – Dermatosis papulosa nigra – ++ –

3.3.1 Asian Skin wrinkling were found to be late and inconspic- uous features of photoaging. Characteristics of cutaneous photodamage Many Asians residing in the Far East are ex- in another Asian population consisting of 407 posed to sunlight year round and are therefore Korean men and women ages 30–92 years were very susceptible to photodamage and accompa- investigated by Chung [27]. Chung identified nying photoaging.Several studies of Asian pop- wrinkling and dyspigmentation as the primary ulations demonstrate pigmentary changes as a characteristics of photoaging in that popula- major component of photoaging. These include tion. Figure 3.4 is an example of both dyspig- facial hyperpigmentation, solar lentigines, and mentation and wrinkling in an Asian woman. pigmented seborrheic keratoses (Fig. 3.3). In a In this study, the number of wrinkles increased study by Goh, the characteristics of photoaging as the age of the individual increased. This was in an Asian population in Singapore, which the case as well for dyspigmentation. In the Ko- consisted of Chinese, Indonesians, and Malay- rean population, dyspigmentation appeared as sians, was described [26]. The population con- two distinct types of lesions: hyperpigmented sisted of 1,500 subjects with skin types III and macules on sun-exposed skin were described, IV. In this population, hyperpigmentation was as well as pigmented seborrheic keratoses. The noted to be an early and prominent feature of number of pigmentary lesions increased as the photodamage. In contrast, coarse and fine age of the individual increased. Gender differ-

Fig. 3.3. Asian populations demonstrate pigmentary changes as a major component of photoaging, including facial hyperpigmentation, solar lentigines and pigmented seborrheic keratoses Photoaging and Pigmentary Changes of the Skin Chapter 3 35

Fig. 3.4. Dyspigmentation and perior- bital wrinkling in an Asian woman

ences in the type of pigmentary lesions were al- mentation, increased severity became apparent so noted. In Koreans greater than 60 years of at 50 years of age, and there was a statistically age, seborrheic keratoses were more common significant association between wrinkling in men than in women. In those 50 years of age grades and dyspigmentation grades. The effect and older, hyperpigmented macules were of excessive sun exposure and cigarette smok- found more frequently in women than in men. ing on wrinkling was found to be multiplicative Women in the fourth decade had an average of in this Korean population. Sun exposure of 4.3 hyperpigmented macules, which increased more that 5 h/day and a smoking history of to 23.5 by the sixth decade and 25.1 by the eighth more than 30 pack-years (when controlled for decade. Men in the fourth decade had an average and gender) were associated with a 4.2-fold age of 0.1 seborrheic keratoses, which increased increased risk for wrinkling compared with a to 4.6 by the sixth decade and 13.6 by the eighth 2.2-fold increase for nonsmokers with 1–2 h/ decade. day of sun exposure. There was, however, no Additionally, Chung established the associa- significant association observed between tion between sun exposure and the develop- smoking and dyspigmentation. ment of wrinkling in the Korean population Kwon reported the prevalence of pigmented [27]. Previously, wrinkling was not felt to be a seborrheic keratoses in 303 Korean males ages major feature of photoaging in Asian popula- 40–70 years [28]. Seborrheic keratoses oc- tions. Chung demonstrated wrinkling in 19.2% curred on sun-exposed areas of the skin, with of Koreans with a daily exposure of 1–2 h com- the majority of lesions concentrated on the face pared with 64.6% of those who had more than and the dorsa of the hands. Similar to Chung’s 5 h/day. Sun exposure of more than 5 h/day was report, the prevalence of seborrheic keratoses associated with a 4.8-fold increased risk for in Kwon’s study was shown to increase by age, wrinkling compared with 1–2 h/day. The pat- with 78.9% of Korean men having seborrheic tern of wrinkling in both sexes was similar, but keratoses at age 40, 93.9% at age 50, and 98.7% there was a greater risk for development of at 60 and older. The mean overall prevalence of wrinkles in women than in men after control- seborrheic keratoses in was 88.1%. Both chron- ling for age, sun exposure, and smoking. In this ological aging and cumulative sun exposure study, with regard to both wrinkles and dyspig- were independent variables for the develop- 36 Susan C.Taylor

ment of seborrheic keratoses. Those Koreans several pigmentary abnormalities observed in with a lifetime cumulative sun exposure of African American skin. Hyperpigmentation as- more than 6 h/day had two times the risk of de- sumes several forms. Focal areas of hyperpig- veloping seborrheic dermatoses than those mentation, either mottled or more confluent, with less than 3 h/day. In summary, in Asian impart an uneven skin tone,which is a common skin, in addition to wrinkling, hyperpigmented cosmetic complaint for African America wom- 3 macules, solar lentigines, and seborrheic kera- en in particular (Fig. 3.6). Another not uncom- toses were the major pigmentary alterations as monly observed type of hyperpigmentation is a demonstrated in several studies. generalized darkening of the facial skin compared with the sun-protected areas (Fig. 3.7). It is known that skin pigmentation increases with 3.3.2 African American Skin exposure to both UVA and UVB radiation. Whereas the production of melanin from the It is well established that melanin confers pro- stimulation of UVB is of short duration, that tection from UV light. Kaidbey demonstrated due to cumulative UVA exposure appears to be increased photoprotection by melanin in black much longer lasting [34]. UVB-induced pig- compared with white skin [29]. The mean pro- mentation disappears with epidermal turnover tective factor for UVB for black epidermis was within a month, in contrast to UVA pigmenta- 13.4 compared with 3.4 for white epidermis. tion that may last several months to a year. The Similarly, the mean protective factor for UVA difference is likely related to the basal local- for black epidermis was 5.7 compared with on- ization of UVA-induced pigment. Long-term ly 1.8 for white epidermis. Given the photopro- UVA-stimulated pigmentation may very well tective effect of melanin, one would anticipate explain the general darkening of the sun-ex- that African Americans would display fewer posed skin frequently observed in African changes associated with photoaging compared Americans. with those individuals with white skin. Hence, Solar lentigines are not a primary compo- African American women often appear young- nent of photoaging in African American skin. er that Caucasian women of the same age This is undoubtedly related to the photoprotec- (Fig. 3.5a,b). Additionally, the onset of the cuta- tive effect of melanin, as discussed previously. neous manifestations of photoaging reportedly Although not formally studied as in Asian skin, occurs at a later age in African Americans com- it has been observed that benign pigmented le- pared with whites [30]. As would be expected, sions are a frequent component of aging in Af- photoaging in African Americans in more pro- rican Americas. Seborrheic keratoses are noted nounced in individuals with lighter skin hues on sun-exposed as well as sun-protected skin. [31]. Long-term sun exposure to African Amer- Dermatosis papulosa nigra (DPN), a type of ican skin does not produce the readily apparent seborrheic keratosis, is prominent only on the characteristics of photoaging observed in white sun-exposed facial skin of both African Ameri- skin. For example, wrinkling beside the lateral can men and women. It is theorized that chron- canthi of the eyes and at the corners of the ological aging and cumulative sun exposure are mouth occurs less often in African Americans variables for the development of DPNs. compared with whites [32]. Montagna also Disorders of hypomelanosis are readily ap- found that shrinkage and reduction of dermal parent in African Americans, given the contrast volume leading to sagging of the facial skin oc- between the normally pigmented skin and the curred less precipitously in the facial skin of contrasting white area. Guttate hypomelanosis young and middle-aged black women. is characterized by multiple, small, depigment- Photoaging features most often apparent in ed macules on the anterior surface of the legs, the African American population include fine lower abdomen, and arms [35]. The macules are wrinkling, skin textural changes, benign cuta- circular with well-defined borders. The diffe- neous growths, and pigmentary abnormalities rential diagnosis in this group would include [33]. Although not well characterized, there are vitiligo. Photoaging and Pigmentary Changes of the Skin Chapter 3 37

Figs. 3.5a,b. An African American women who appears younger that a Caucasian women of the same age

In summary, in African American skin, dis- 3.3.3 Caucasian Skin crete and confluent hyperpigmentation, seborrheic keratoses, dermatosis papulosa nigra, and Wrinkling and dyspigmentation are commonly idiopathic guttate hypomelanosis are the major observed features of photoaging in Caucasian pigmentary alterations demonstrated. skin (Fig. 3.8). Warren studied photoaging in Caucasian women ages 45–51 with skin types I–III who resided in an area of intense sunlight: Arizona [36]. The investigators, after viewing photographs of nine Caucasian women who had received more than 12 h/week of sun expo- 38 Susan C.Taylor

Fig. 3.6. Focal areas of hyperpigmentation, either mottled or confluent, impart an uneven skin tone to the faces of many Af- rican America women 3

Fig. 3.7. A generalized darkening of the facial skin compared with the sun-protected areas of the upper chest and shoulders in this African American woman

sure for 10 years’ duration, estimated their mean and lines (wider that 0.5 mm and longer that age to be 58.2 years. This contrasts with an esti- 5.0 mm) was summed for each group. Sun expo- mated mean age of 53.7 years for 13 Caucasian sure increased the total wrinkle length with the women who had experienced less than 2 h/week women with greater exposure for a total wrin- of sun exposure. Additionally, the women with kle length of 75.7 cm compared with the low-ex- more sun exposure had more wrinkles in the posure group, with 53.5 cm total wrinkle length. crow’s feet area as well as on the remainder of Dyspigmentation is a major component of the face compared with those with less expo- photoaging observed in white skin [37]. Dys- sure. In the study, the total length of all furrows pigmentation not readily observable becomes Photoaging and Pigmentary Changes of the Skin Chapter 3 39

Fig. 3.8. Wrinkling and dyspigmentation are commonly observed features of photoaging in Caucasian skin

significantly more prominent under Wood’s Solar or actinic lentigines appear during the light examination or UV photography. Discrete forth through sixth decades in sun-exposed and mottled hyperpigmentation under normal skin. They are a readily apparent sign of photo- and UV photography is seen in Fig. 3.9a,b, aging in white skin and appear on the face, which are courtesy of George Faraghan, Fara- chest, extensor forearms, and dorsa of the ghan Medical,Philadelphia,PA,USA.One of the hands (Fig.3.10).There is variation in their size, manifestations of dyspigmentation in photo- ranging from several millimeters to over a cen- aged white skin is mottled, irregular areas of timeter, as well as in the regularity of their bor- pigmentation [38]. The mottled appearance ders. The incidence of solar lentigines increases correlates with areas of hyperpigmentation with age, affecting more than 90% of whites with irregular distribution of melanocytes older than 50 years [37]. They are related to a along the basement membrane. This is asso- tendency to freckling and sunburns after the ciated with a heterogeneous distribution of age of 20 years [40]. They are usually numerous melanosomes within the keratinocytes and ad- and may be accompanied by adjacent patchy jacent areas of hypopigmentation with de- hypopigmentation, which involves a decrease creased melanocytes and melanosomes [39]. in the number of melanocytes associated with a Another manifestation–freckles, or ephe- reduction in the production of mature melano- lides–are small, brown macules on sun-ex- somes. This results in a mottled appearance of posed skin that darken and increase in number the skin [41]. Lentigines darken significantly af- with more intense sun exposure during the ter exposure to sunlight [42]. The differential summer months. They appear in fair-skinned diagnosis of lentigines includes other pigment- individuals and genetically predisposed chil- ed lesions, including lentigo maligna, pigment- dren. Pigmented seborrheic keratoses occur as ed actinic keratoses, pigmented basal cell carci- a manifestation of aged skin but seemingly oc- nomas, and flat or macular seborrheic keratos- cur less frequently on sun-exposed white skin es. Whereas solar lentigines occur in all skin compared with Asian skin. Likewise, dermato- types, the reticulated black solar lentigo occurs sis papulosa nigra also appear to occur less of- primarily in sun-exposed skin of very fair- ten in white skin compared with African Amer- skinned whites [43]. It resembles a spot of ink ican skin. on the skin with irregular margins and a retic- 40 Susan C.Taylor

Fig. 3.9a,b. Discrete and mottled hyperpigmentation under normal photography (a) and ultraviolet (UV) photography (b). Photographs are courtesy of George Faraghan, Faraghan Medical Photography, Philadelphia, PA, USA

Fig. 3.10. Solar lentigines and other pigmentary manifestations of photoaging on the chest of a Caucasian woman Photoaging and Pigmentary Changes of the Skin Chapter 3 41 ular pattern. Black solar lentigines are consid- stratum corneum of photodamaged skin was ered a rare variant of actinic lentigines. They compact and laminated. The corneocytes were are few in number in contrast with the large plump, with amorphous material between and number of lentigines, and they must be distin- at times inside the corneocytes. The transition guished from melanoma. between the stratum lucidum and the stratum Hypomelanosis is observed in Caucasian corneum was often indistinct. The stratum lu- skin, although it may not be as readily apparent cidum was thicker compared with normal epi- in white skin. Guttate hypomelanosis is charac- dermis, with two or more cell layers. Large ves- terized by multiple, small, depigmented ma- icles containing proteinous material were not- cules on the anterior surface of the legs, lower ed. Numerous changes were noted in the epi- abdomen, and arms [44]. The macules are cir- dermis, as well. These included cell heterogene- cular with well-defined borders.In summary,in ity, vacuolization, dysplasia, and necrosis. The white skin, in addition to wrinkling, ephelides, epidermal cells were noted to be in disarray, lentigines, and mottled hyperpigmentation with atypical shape,size,and/or staining as well were the major pigmentary alterations demon- as loss of polarity. Necrotic cells were observed strated in several studies. in the epidermis, with single dying or dead cells. The epidermis contained intercellular and intracellular vacuoles in the basal and spinous 3.4 Histology of Photoaged Skin layers. These vacuoles distorted both basal cells and melanocytes. Large, pale, staining cells were Several investigators have evaluated the histo- present in the spinous layer. Fewer Langer- logical changes associated with photodamaged hans cells were present in severely photodam- skin in various racial groups and utilizing vari- aged skin compared with normal skin. Dysker- ous techniques [45, 46, 47, 48]. Characteristics atotic or stem cells were present in the basal identified are different from those found in in- layer. The periodic acid-Shiff (PAS) positive trinsic or chronological aging [23]. In intrinsic basement membrane was distinctly crinkly as it aging, there is both epidermal and dermal atro- followed the extensions of the basal cells. phy, with flattening of the dermal-epidermal Empty vesicles formed a foamy layer beneath junction. Epidermal atrophy is due to the re- the basement membrane. In regard to pig- duction of keratinocytes in the rete ridges, as mentary changes of photodamaged skin, basal well as melanocytes and Langerhans cells. and suprabasal keratinocytes contained more There is loss of the undulating pattern of the melanosomes in both photoaged and normal dermal-epidermal junction. Dermal atrophy is skin. In darkly pigmented areas of the skin, attributed to loss of fibroblasts, elastic fibers, melanosomes were present in all of the ke- vasculature, and appendages. In adults, the ratinocytes and corneocytes. In the papillary amount of collagen decreases by 1% per year and lower intermediate dermis, elastic fiber due to decreased collagen synthesis and in- masses were noted. Areas with advanced elas- creased collagenase mRNA [49, 50]. A loss of tosis were found to be next to areas with fewer elastic fibers occurs with fragmentation of elas- elastotic changes. In areas with enlarged, tin fibers. The loss of skin appendages is due to knotted, elastic fibers and rounded elastotic a decrease in the number of hair follicles and in masses, fragmentation of fibers was observed. eccrine and apocrine gland size. There is also a The lower papillary and upper intermediate decrease in the number of melanocytes in the dermis of sun-exposed skin had numerous hair bulb. reticulin fibers accompanying the fibers of the Montagna reported the histology of photo- elastotic masses. Small collagen fibers were damaged facial skin of 200 Caucasian women noted in the papillary dermis. The grenz zone ages 21–55 who resided in an area of intense that replaced the papillary dermis consisted of sunlight: Arizona [45]. Changes were noted small fibers horizontally oriented. Elastotic throughout all layers of the skin, including the material appeared to crowd out the collagenous stratum corneum, epidermis, and dermis. The fibers. 42 Susan C.Taylor

Warren’s group also studied photoaging in changes are responsible for the development of Caucasian women [46]. They evaluated histolo- pigmentary changes and cancerous changes. gy, actinic elastosis, and collagen in four groups Histological evaluation of photoaged black of Caucasian women ages 45–51 with skin types and Asian skin has also been performed [47,51]. I–III who resided in Arizona. The groups were Compared with white skin, striking differences divided according to age (younger versus older) were noted in individuals with black skin. In 3 and sun exposure (low versus high). Skin color, one group of Asians from Thailand, marked erythema, and darkness were evaluated using similarities were noted between white skin and the CIE L*, a*, b* color scale. No differences in Asian skin [47]. Montagna performed a histo- skin color with respect to skin redness and logical analysis of sun-exposed skin of 19 black darkness were identified among the four and 19 white women [51]. He reported dramatic groups. However, other histological character- racial differences in the skin of whites and istics of photoaging were identified. The older blacks after long-term sun exposure. Overall, women had a statistically significant more elas- the epidermis of black skin showed only minor tosis than the younger women. Additionally, changes compared with the profound altera- elastosis was more significant in the older tions that occurred in white skin. Histological women with high sun exposure compared with analysis of the skin of many of the 19 black the older low-sun-exposure group. The older women analyzed revealed an entirely normal high-sun-exposure group had more elastin and epidermis.In the others,vacuoles and dyskerat- decreased dermal collagen than the older low- osis were present in the keratinocytes of the sun-exposure group. A grenz zone was present malpighian layer. These alterations were re- in the dermis of all older women regardless of ported to be similar to those observed in white sun exposure. There were no changes in epider- skin. However, white epidermis showed more mal thickness related to solar exposure. dramatic changes, with many focal areas of Electron microscopic characteristics of pho- atrophy and/or necrosis. In contrast, atrophy toaging in white skin were evaluated by Toyoda was observed in only one of the 19 black wom- [48]. He demonstrated both qualitative and en ages 22–50, and it was mild in that case. The quantitative differences between photoaged stratum lucidum in undamaged skin, white or and intrinsically aged facial skin. There were black, consisted of one or two thin layers, and several characteristics of sun-exposed facial the stratum granulosum rarely exceeded three skin that were statistically significant com- layers. However, in white skin, on exposure to pared with sun-protected skin. Some of these UV light, the stratum lucidum was distorted. It differences included increased keratinocyte was swollen, with increased cell layers. In con- and melanocyte heterogeneity, electron lucent trast, the stratum lucidum in black skin rarely degeneration of epidermal and peri-infundibu- showed any sign of alteration and remained lar keratinocytes, melanocytes with vacuolar compact and unaltered. structures, dermal melanophages, reduplica- Montagna’s data demonstrated that the en- tion of the basal lamina of the epidermis, de- tire epidermis of blacks, including the stratum generated microfibrils, solar elastosis, active granulosum, lucidum, and corneum, contained mast cells, and decrease in normal microfibril melanosomes in both the younger and older bundles. Regarding melanocyte damage, irreg- age groups. In white skin, only a few melano- ularly shaped nuclei and electron-dense cyto- somes were seen in the basal layer. Melano- plasm in sun-exposed skin compared with sun- phages in black dermis were more numerous protected skin were noted. Semiquantitative and larger that in white dermis. Melanophages evaluation revealed a significant increase in were observed to become progressively smaller melanocytic heterogeneity in sun-exposed in the deeper dermis. The melanophages in skin. Vacuolar structures in melanocytes were black skin contained membrane-bound com- identified, and the degree of vacuolization was plexes of melanosomes. commensurate to the severity of the degenera- Black skin reportedly has a thick and com- tion of keratinocytes. It is likely that these pact dermis with an indistinct intermediated Photoaging and Pigmentary Changes of the Skin Chapter 3 43 layer in contrast to the distinct layer in white fa- 3.4.1 The Pigmentary System cial skin. In black dermis, there was close stack- in Photoaged Skin ing of the collagen bundles, which ran parallel to the surface of the epidermis. Collagen fiber bundles in the dermis were smaller than those The aging process, both intrinsic and extrinsic, found in white skin. In contrast to white skin in produces a variety of responses by melanocy- which they were sparse, there were many colla- tes. These processes are both inhibitory and gen fiber fragments in the dermal interstices. stimulatory. It has been established that the Elastosis, a hallmark of photoaging in white number of dopa-positive melanocytes decreas- skin, was not observed in the specimens of any es with age by approximately 10–20% per of the black subjects. In contrast, in white skin, decade [52, 53]. The decrease in melanocyte variable amounts of moderate-to-extensive number occurs in both sun-exposed and sun- elastosis were observed. White skin always had protected areas of the skin. This, along with a more elastic fibers in the dermis compared loss in the skin’s vasculature, would explain the with black skin. Dermal changes were observed pale appearance of intrinsically aged skin. in the older black subjects. There was an in- However, with long-term sun exposure, the crease in the number and thickness of elastic fi- density of melanocytes increases and is ap- bers in the reticular dermis. Elastic fibers, con- proximately two-fold higher than in sun-pro- figured in single strands in younger black sub- tected skin [25]. The molecular events underly- jects, appeared in thicker braid-like configura- ing the action of UV radiation on melanocytes tions in 50-year-old subjects. Elaunin fibers in are largely unknown [38]. In vitro, multiple ex- black skin did not form the candelabra-like posures to UV radiation inhibit melanocyte structures found in white skin but were config- growth [54, 55]. Melanocytes irradiated with ured in a parallel or angular array to the epider- UVB are known to be blocked in the G1 phase mis. Oxytalan fibers in older black women were of replication. However, the situation in vivo is intact in contrast to those of older white wom- different. After UV exposure, melanocyte den- en. sity increases, as demonstrated by Quevedo. In Kotrajaras studied photodamage and the ef- his study, the number of melanocytes increased fect of topical treatment in a population of 61 when buttock skin was irradiated with UV light Asian women of Thai descent. These women, [52]. Melanocytes are thus influenced by a with skin type IV, had a history of substantial number of factors, some of which increase their UV exposure [47]. Histology revealed epider- number and production of melanin. These fac- mal atrophy, atypia, and dysplasia. The kerati- tors include cytokines and growth factors, nocytes in the basal layer of the skin had dense which are stimulated with UV exposure and in- clusters of highly melanized melanosomes. clude interleukins 1, 6, and 8, TNF-alpha, TGF- There was an overall increase in melanin in the beta, BFGF, growth factor, endothelin deriva- keratinocytes. Many large, pigment-laden me- tives, and nerve growth factor [56, 57, 58, 59]. lanophages were identified in the dermis, in- These cytokines and growth factors have a di- cluding the reticular dermis, of the majority of rect effect on melanocyte proliferation and sur- the women.Additionally, in the dermis, marked vival and play a role in the pathogenesis of pig- elastosis presenting as twisted fibers in various mentary changes of photoaged skin [38]. Addi- stages of amorphous degeneration were noted. tionally, inflammatory mediators formed dur- Elastotic tissue almost completely replaced the ing UV exposure, such as leukotriene C1,stimu- collagen network. late growth of melanocytes and modifications in the normal melanocyte phenotype [60]. Histological features of the pigmentary change associated with photoaging, including mottled hyperpigmentation, ephelides, solar lentigines, seborrheic keratoses, and guttate hypopigmentation, have been investigated. Areas 44 Susan C.Taylor

of mottled hyperpigmentation correlate with mal-epidermal junction and a 10–55% reduc- an irregular distribution of melanocytes along tion in the number of dopa-positive keratinoc- the basement membrane. Melanocytes display ytes [37]. Ultrastructurally, the melanosomal increased dopa-positivity,and there is a hetero- content of the epidermal keratinocytes is vari- geneous distribution of melanosomes within able with some containing numerous melano- the keratinocytes [39]. Ephelides display hyper- somes and others containing only immature 3 pigmentation of the basal cell layer without el- melanosomes. ongation of the rete ridges. It has been demonstrated by light and electron microscopy that ephelides have fewer melanocytes than adja- 3.5 Overview of Prevention cent, paler skin [38]. However, the melanocytes of Photoaging and Pigmentary of ephelides,which are large and strongly dopa- Changes of the Skin positive, produce eumelanosomes and hence darker eumelanin whereas in adjacent, paler skin, melanocytes often produce pheomelano- It is now well established that UV exposure is somes and lighter pheomelanin [39]. the basis of photoaging in all skin types. The Solar lentigines, a hallmark of photoaged pigmentary aspect of photoaging as well as all skin, are characterized histologically by an in- other manifestations may be prevented by lim- crease in melanocytes and melanin synthesis. iting exposure to UV light. This may be There is hyperpigmentation of the basal cell achieved through sun avoidance and the use of layer with elongation of the rete ridges.The rete protective clothing, hats, and sunglasses. The ridges are club shaped or have bud-like exten- judicious use of sunscreen to block both UVA sions [61]. There is an overall increase in the and UVB is an important preventative measure number of melanocytes. Electron microscopic for photoaging. Thus, the selection of a broad studies demonstrate an increase in the activity spectrum sunscreen with ingredients that of melanocytes, as well. The melanocytes are block the action spectrum of UVA (oxyben- normal with no cytological atypia,although the zone, avobenzone) and UVB (paraaminoben- nuclei are irregularly shaped [38]. Large num- zoic acid, octyl methoxycinnamate, and octyl bers of melanosomes are observed in kerati- salicylate) or a physical blocker containing tita- nocytes as well as in the stratum corneum. nium dioxide or zinc oxide is essential. Braun-Falco suggested that in the lentigo, there Antioxidants most likely play a role in pre- may be a possible abnormality in the lysosomal vention of photoaging as well. The mechanism degradation of pigment granules within the by which this occurs has been demonstrated in epidermal keratinocyte [62]. A reticulated vivo by Kang [63]. In the first part of the experi- black solar lentigo, a black macule with an ir- ment, UV irradiation was demonstrated to in- regular outline, histologically displays lentigi- crease the levels of the free radical hydrogen nous hyperplasia with elongation of the rete peroxide in the skin. Next, the action of antiox- ridges and hyperpigmentation of the basal idants on free radicals was evaluated. It was layer with skip areas [43]. Melanocytes are not demonstrated that the antioxidants genistein especially numerous, but they show thicker and (an isoflavone found in soybeans) and N-acetyl more prominent dendrites. cysteine (NAC) (an amino acid derivative that Pigmented seborrheic keratoses, another le- is converted into the antioxidant glutathione) sion observed in photoaged skin, has variable were not able to block UVB and thus did not amounts of melanin pigmentation. Melanocy- have sunscreen properties. Instead, genistein tes are present in the basal layers of seborrheic and NAC interrupt the UV signaling cascade in keratoses and in suprabasal locations. Melano- human skin that leads to photoaging. Genistein somes are transferred to epidermal keratinocy- was found to block the activation of epidermal tes and are found predominantly in the kerato- growth factor-receptor (EGF-R) and the MAP sis. Guttate hypomelanosis of aging is charac- kinase pathway, which leads ultimately to the terized histologically with flattening of the der- formation of MMPs and the breakdown of ex- Photoaging and Pigmentary Changes of the Skin Chapter 3 45 tracellular matrix components. NAC did not problem with this study is that the mechanism block activation of EGF-R but, instead, in- of action of the antioxidant, ascorbate, is in the creased the levels of reduced glutathione in hu- prevention of photoaging as opposed to the man skin. UV also stimulates the ERK pathway, treatment of photoaging. Therefore, it seems and genistein and NAC both inhibited UV in- unlikely that an antioxidant will treat existing duction of ERK activity. As for the other path- photodamage. way, UV stimulates JNK phosphorylation. NAC did not effect UV induction of JNK phosphorylation, but genistein did block the phosphoryla- 3.6 Overview of Treatment tion of JNK. Genistein and NAC inhibited the of Photoaging and Pigmentary induction of cJun protein and inhibited the UV Changes of the Skin induction of collagenase mRNA. Thus, the UV signaling cascade in human skin that leads to photoaging is interrupted by genistein and There are three categories of treatment types NAC. for photoaging and pigmentary changes: The antioxidants ascorbic acid and alpha-tocopherol are used in a variety of products that claim to prevent photoaging. The effects of í Therapeutic modalities to improve pig- three forms of topically applied tocopherol mentary changes induced by UV light, were studied on UV-radiation-induced free which can be divided into topical agents radical formation in a mouse model [64]. To- and procedural agents copherol sorbate was shown to significantly de- í Topical agents, which include retinoids, crease the UV-radiation-induced radical flux in hydroquinones, and combination thera- skin. It was also found to be significantly more pies protective against skin photoaging than alpha- tocopherol and tocopherol acetate. Translation í Procedural agents, which include chemi- from an animal model to human skin is in- cal peels, microdermabrasion, lasers, inferred. Ascorbic acid is also a popular ingredi- tense pulse light, and cryotherapy ent in anti-aging medications. Topical vitamin C was studied in a porcine skin model [65].An- imals treated with topical ascorbic acid exhibit- There are a myriad of therapeutic modalities ed fewer sunburn cells than did those animals that can improve the pigmentary components treated with vehicle after exposure to UVA and of photoaging. These modalities may be divid- UVB, and there were decreases in erythema in ed into topical agents and procedural agents. vitamin-treated areas. It must be noted that an Topical agents include retinoids, hydroqui- in vitro model does not prove similar results in nones, and combination therapies. Procedural human skin. In currently available products, agents for the treatment of pigmentary abnor- there is uncertainty as to the actual amount of malities include chemical peels, microderma- antioxidant contained therein and in the stabil- brasion, lasers, intense pulse light, and cryo- ity of the antioxidant. Furthermore, the percut- therapy. Some of the therapeutic modalities are aneous absorption through human skin of the better suited for certain skin types (Table 3.3).A antioxidant is often unknown. Remembering brief overview of these agents will be provided that the theoretical role of the antioxidants is a with an emphasis on published clinical trials preventative one, Traikovich determine the effi- that support the efficacy of the particular mo- cacy of topical ascorbic acid in the treatment of dality.A more exhaustive review of each modal- mild-to-moderate photodamage in the facial ity appears throughout this book. skin of 19 subjects over a 3-month period [66]. The leading topical agents for the treatment He demonstrated a significant improvement in of photoaged skin, including pigmentary ab- skin surface textural changes after the use of normalities, are the retinoids. In double-blind ascorbic acid versus the control group. The controlled trials, it has been demonstrated that 46 Susan C.Taylor

Table 3.3. Treatment of pigmentary characteristics of photoaging in Asian, African American, and Caucasian skin

Treatment modality Asian African American Caucasian

Sunscreen ++ ++ ++ Antioxidants ++ ++ ++ 3 Retinoids ++ ++ ++ Hydroquinones ++ ++ ++ Chemical peels + + ++ Microdermabrasion ++ ++ ++ Cryotherapy + – ++ Laser + – ++ Intense pulse light + + +

the three retinoids available in the United epidermal pigment and clinical lightening of States, tretinoin, adapalene, and tazarotene, ef- the pigmented lesions. In a primarily African fectively lighten pigmentary abnormalities as- American population, Bulengo-Ransby demon- sociated with photoaging. Weiss demonstrated strated improvement in pigmentation with lightening of lentigines and other hyperpig- 0.1% topical tretinoin cream. This improve- mented areas on the face and forearms of 30 ment was not with photoaging-associated pig- subjects who applied 0.1% tretinoin cream dai- mentation but with that seen in postinflamma- ly compared with vehicle for 4 months [67]. As tory hyperpigmentation. Fifty-four subjects an extension of that trial, Ellis demonstrated were treated for 40 weeks with a daily applica- further improvement in hyperpigmentation as tion of 0.1% tretinoin cream [71]. Significant well as the other parameters of photoaging over improvement was demonstrated in the treti- a 6-month period with topical tretinoin applied noin group,with 91% of that group demonstrat- daily to the face and forearm [68]. Rafal evalu- ing lighter or much lighter pigmentation com- ated the efficacy of topical tretinoin in the pared with 57% of the vehicle group. Epidermal treatment of lentigines associated with photo- melanin content decreased 23% in the tretinoin aging [69]. Tretinoin in a 0.1% concentration group compared with 3% of vehicle group. was applied to the faces of 58 subjects in this 10- Adapalene gel in either a 0.1% or 0.3% con- month study. Clinical lightening of solar lenti- centration was used for 9 months in the treat- gines was noted in 83% of the treated facial le- ment of both actinic keratoses and solar lenti- sions compared with 29% of controls. Histolog- gines in 90 subjects [72]. One month of adapa- ical analysis revealed a 35% decrease in epider- lene use resulted in significant lightening of so- mal pigmentation in the treated group com- lar lentigines compared with the control group. pared with a 34% increase in the vehicle-treated At 9 months, nearly 60% of subjects had light- group. Griffiths examined the efficacy of 0.1% ening of the lentigines compared with 36% of tretinoin cream for 4 weeks in 45 Asians with the control group. hyperpigmented lesions on the face and hands The efficacy of tazarotene cream at a con- [70]. Each subject had at least four lentigines on centration of 0.1% for the treatment of facial the face and/or hands. Hyperpigmented lesions photodamage was evaluated in 563 subjects were lighter or much lighter in 90% of the pa- over an initial 24-week period followed by a 28- tients receiving tretinoin compared with 33% of week extension [73]. Improvement in pigmen- controls. Histology demonstrated a 41% de- tary appearance was the first change to be not- crease in epidermal pigmentation in the treated ed in the tazarotene group, with mottled hy- group compared with a 37% increase in the perpigmentation showing a statistically signifi- control group. There was a statistically significant improvement over vehicle after 2 weeks of cant correlation between decrease in histologic therapy. Lentigines and irregular dyspigmenta- Photoaging and Pigmentary Changes of the Skin Chapter 3 47 tion improved over 4 weeks. Pigmentation con- solar lentigines on the forearm, dorsum of the tinued to improve as treatment continued. hands, and the face twice daily. The combina- Hydroquinones are the mainstay of treat- tion product was statistically superior in the ment for most disorders of hyperpigmentation. lightening of lentigines to each of its active However, there is a paucity of trials examining components or vehicle. the efficacy of hydroquinone in the treatment Cryotherapy is an often-used procedural of photoaged skin, including solar lentigines, modality for the treatment of pigmentation in mottled hyperpigmentation, and diffuse hyper- photoaged skin, particularly for lentigines. The pigmentation. Clinical studies using hydroqui- mechanism of action of cryotherapy is the de- none for the treatment of various other pig- struction of melanocytes on exposure to cold mentary abnormalities have been published. temperatures. Cold temperatures may be ob- These include studies of postinflammatory hy- tained through the use of liquid nitrogen or, perpigmentation and melasma. Results appli- less commonly, carbon dioxide or nitrous ox- cable to photoaging may be inferred from these ide,which are applied to the skin via direct con- trials. Sanchez and Vasquez, among others, tact or with a spray device. Two studies support demonstrated significant improvement in me- the efficacy of cryotherapy in the treatment of lasma using 3% hydroquinone in the treatment solar lentigines. Almond-Roesler reported the of 46 women with melasma [74]. Ruiz-Maldo- successful treatment of solar lentigines by nado recommended hydroquinone in the con- brief, gentle cryosurgery using a Kryomed de- centration of 2–4% for the treatment of postin- vice in 20 patients [79]. Lentigines on the hands flammatory hyperpigmentation for 3 to 6 of 80–100% of the subjects demonstrated light- months [75].Glenn demonstrated that 6% hy- ening. Zouboulis reported resolution of lenti- droquinone solution produced a statistically gines in 6 subjects treated with nitrous oxide significant lightening in various pigmentary [80]. In addition to the destruction of melanoc- disorders compared with 3% hydroquinone ytes comprising the lentigo, adjacent and sub- [76]. The pigmentation associated with photo- adjacent melanocytes may be destroyed or in- aging requires the application of the hydroqui- jured, resulting in lesional and/or perilesional none twice daily directly to the area of involve- depigmentation, hypopigmentation, or hyper- ment for 3 months. pigmentation. In a study using liquid nitrogen The efficacy of combination therapy in the cryotherapy to lentigines on the dorsum of the treatment of solar lentigines and hyperpig- hands in ten subjects, 50% of the treatment mentation has been reported for the combina- group experienced hypopigmentation at 6 tion of tretinoin/hydroquinone and the combi- months posttreatment [81]. Therefore, given nation of 4-hydroxyanisole/tretinoin. Experi- the unpredictability of the response with cryo- ence with the combination of 5% hydroquinone therapy, this modality is limited to the treat- and tretinoin (0.1–0.4%) was reported by ment of solar lentigines in lightly pigmented Yoshimura in 136 Asian subjects who applied individuals. the combination to face, trunk, and lower ex- Laser selection and techniques and intense tremities for treatment of hyperpigmentation, pulse light for treatment of photoaging is dis- including lentigines [77]. After 8 weeks, 82% of cussed extensively in Chap. 3. Briefly, many la- the patients had a good to excellent result. sers have the capability of treating pigmenta- However, postinflammatory hyperpigmentation associated with photoaging but not in all tion was observed in some patients. Fleischer skin types. The superficially located melanin reported the results of the combination of 2% pigment in solar lentigines lends them to treat- 4-hydroxyanisole and 0.01% tretinoin in the ment with the rapid-firing Q-switched lasers, treatment of solar lentigines and related hyper- including the Q-switched ruby, alexandrite, and pigmented lesions in two double-blind multi- Nd:YAG. Inappropriate destruction of mela- center trials of 24 weeks’ duration [78]. The nocytes remains a potential problem for darker combination product, a vehicle, and each of the skin types. Therefore, laser therapy is infre- active ingredients individually were applied to quently used in darker skin types. Kopera re- 48 Susan C.Taylor

ported the fading of 196 solar lentigines in eight gines on the faces of 20 subjects [87]. Forty per- women after treatment with the Q-switched ru- cent had complete remission, 50% partial re- by laser [82]. One treatment resulted in lesion mission, and 10% no response after a total of improvement without adverse results. Rosen- eight treatments administered every 2 weeks. bach treated 21 lentigines in 11 patients with the The addition of trichloroacetic acid to micro- Q-switched alexandrite laser [83]. Sixteen le- dermabrasion did not substantially improve 3 sions had a good, excellent, or complete re- the results in that study. sponse. In that study, patients with skin types Superficial, medium, and deep chemical IV were included, and no hypopigmentation or peels may be employed for the treatment of pig- hyperpigmentation was reported. Chan report- mentary abnormalities associated with photo- ed treating 34 Asian patients with solar lenti- aging. The specific agents used include glycolic gines with three types of Nd:YAG 532 lasers: the acid (35–70%), salicylic acid (20–30%), trichlo- Versapulse Q-switched Nd:YAG 532, the Versa- roacetic acid (10–25%), and combination peels, pulse longpulse Nd:YAG 532 nm, and a conven- including Jessner’s solution (14% salicylic acid, tional Q-switched Nd:YAG 532 [84]. Improve- 14% lactic acid, 14% resorcinol in 95% alcohol) ment in the lentigines was graded on a 10-point and trichloroacetic acid, glycolic acid and tri- scale and ranged from 4.50–4.78.A range of ad- chloroacetic acid, and CO2 and trichloroacetic verse events occurred with all three lasers, in- acid. Lugo-Janer treated lentigines on the cluding hyperpigmentation, hypopigmenta- hands of 25 subjects with 30% trichloroacetic tion, and erythema. However, the adverse acid [88]. An improvement of 50% or more was events were most pronounced with the Versa- reported in 47% in the trichloroacetic acid pulse Q-switched Nd:YAG 532. The resurfacing treated group. Improved efficacy was noted lasers, the CO2 and Er:YAG, will treat both with the addition of liquid nitrogen cryothera- wrinkles and pigmentary changes associated py with 71% of subjects displaying 50% im- with photoaging. Again, they are not appropri- provement. Improved efficacy was reported in ate for darker skin types given the risks of post- lighter skin types than darker skin types. Simi- inflammatory hyperpigmentation. larly, a study by Li demonstrated improvement Intense pulse light has been utilized for the in lentigines after treatment with 35% trichlo- treatment of lentigines and vascular lesions as- roacetic acid [89]. sociated with photoaging.The experience of intense pulse light in the treatment of photoaging in Asian skin has been reported by Negishi, 3.7 Summary who determined the effectiveness of photorejuvenation for Asian skin types IV-V using in- Photoaging induced by repeated exposures to tense pulse light [85]. Ninety-seven patients re- UV light produces dramatic changes in the ceived three to six treatments using 550 nm and skin. These changes include fine and coarse 570 nm cutoff filters. A rating of good or excel- wrinkling, precancerous and cancerous lent was given to more than 90% of patients for growths, and pigmentary alterations, to name pigmentation. No long-term adverse events just a few. Pigmentary alterations are a major were reported. Kawada examined the efficacy component of photoaged skin in all skin types. of intense pulse light in the treatment of lenti- However, there is variability in the severity and gines in Asian subjects [86]. Forty percent of manifestations of photoaging between Asians, those patients with lentigines demonstrated a African Americans, and Caucasians due to epi- 50% improvement with treatment. dermal melanin content and melanosomal dis- Superficial exfoliation of the upper layer of tribution The pigmentary alterations most the skin is a strategy used to treat pigmentary commonly associated with photoaged skin are disorders of photoaging. This is achieved with mottled, focal, and confluent hyperpigmenta- either microdermabrasion or chemical peeling tion; ephelides; lentigines; pigmented sebor- agents. Cotellessa examined the efficacy of rheic keratoses; and dermatosis papulosa ni- treatment with microdermabrasion of lenti- gra.Advances in invasive and noninvasive ther- Photoaging and Pigmentary Changes of the Skin Chapter 3 49 apeutic modalities for the treatment of photo- 18. 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