The pigmentary system is modified by the aging process and uneven pigmentation is one of the major changes associated with aging. This article reviews the clinical, histological and ultrastructural changes of the pigmentary system that are associated with senescent skin.
Aging of the skin is a basic biologic process that results from genetic programming — or intrinsic aging — and cumulative environmental damage. Intrinsic aging can be attributed to the passage of time, which is universal and inevitable. Most aging theories discuss the imbalance between DNA damage and repair ability. A current aging theory1 suggests that cumulative oxidative damage to DNA is due to the continuous generation of free radicals. Although there are many antioxidant molecules in the skin (eg, ascorbate, vitamin E, carotenoids, coenzyme Q10, superoxide dismutases, catalase and glutathione peroxidase), they are less effective and deteriorate with advancing age. Photoaging is caused by the effects of cumulative, prolonged sun exposure coupled with intrinsic aging. It results in damage and an inflammatory response. However, a thorough discussion of the mechanisms associated with aging is beyond the scope of this review. This article will focus on the age-related changes of the melanin pigmentary systems in the skin, hair and nails.
There are numerous pigmentary disorders associated with the aging process. Melanin may increase (eg, solar lentigo) or decrease (eg, idiopathic guttate hypomelanosis, graying of hair) with advancing age.2 Pigmentary disorders like melasma and lentigines may significantly impact a patient’s quality of life and psychological well being. According to Taylor et al,3 47.3% of patients with pigmentary disorders admitted feeling self-conscious about their skin, 32.7% felt unattractive because of their skin and 32.7% made an effort to hide pigment changes. In addition, some pigmented lesions are premalignant or malignant. Thus, physicians should be familiar with these pigmentary changes.
Melanocyte in Aged and Photoaged Skin
Approximately 1% to 2% of all epidermal cells are melanocytes, which are also the source of melanin. In sun-exposed skin, melanocyte density is about two times higher than skin that has not been exposed to the sun.4-6 The number of melanocytes in both sun-exposed and unexposed skin decreases by 8% to 20% per decade after age 30.7
In vivo, repeated exposure to UV radiation stimulates melanocyte growth. This occurs because UV radiation results in the up-regulation of interleukin 1, interleukin 6, interleukin 8, tumor necrosis factor α, transforming growth factor β, basic fibroblastic growth factor, endothelin derivatives and nerve growth factor, the last of which is secreted by keratinocytes.8-10 These keratinocyte-derived molecules have a direct effect on melanocyte proliferation and survival. They may also play a role in the pathogenesis of dyspigmentation of photoaged skin. Inflammatory mediators like leukotriene C1 stimulate melanocyte growth and modify melanocyte phenotype, which may help explain melanocyte oncogenesis.11
Many structural changes occur to the melanocytes in photoaged skin, including nuclear heterogeneity, abundant cytoplasmic organelles and elongation of dendrites. The signs of cell activation (eg, increased melanogenesis and large melanosomes) are also seen. Cytomorphometric measurement has revealed significant decreases in cell and nuclear sizes, increases in cell and nuclear perimeters and higher degrees of nuclear ellipticity in sun-exposed melanocytes.6
Pigmentary Changes Associated with Chronological Aging
Changes in the pigmentary system due to aging alone are minimal. Clinically, intrinsically-aged Caucasian skin is pale, due to loss of melanogenic capacity and decrease vascularity.12 The changes of skin pigmentation in intrinsically-aged skin is similar among skin types.13
Seborrheic Keratosis and Dermatosis Papulosa Nigra
Many of the pigmentary changes seen in individuals as they age include pigmented growths on the face, neck and body. Seborrheic keratoses (SKs) and dermatosis papulosa are some of the most common problems. Seborrheic keratosis is a common, benign neoplasm that first appears between the third and fifth decades and increases in size and number with age. SKs have been suggested to be the best biomarker of intrinsic aging in the skin.12 Seborrheic keratoses are characterized by flat-topped, sharply demarcated papulonodular lesions with a velvet to fine verrucous surface (Figure 1, left). The initial size is usually less than 1 cm, but the lesion can grow to several centimeters. With time, the lesion becomes thicker with a “stuck-on” appearance. The lesion can be light brown to deeply pigmented. Histologic findings include hyperkeratosis, acanthosis, keratin-filled invaginations of the epidermis (horn cysts) and marked hyperpigmentation of the basal layer. The hyperpigmentation observed in SKs is associated with high levels of endothelin-1 (ET-1) produced by the proliferating keratinocytes, suggesting ET-1-induced melanogenesis, dendricity and melanocyte proliferation.10,14-16
Dermatosis papulosa nigras are characterized by multiple, 1 mm to 5 mm dark brown to black flat-topped papules on the face and neck. This condition is common in African American populations, affecting approximately 77% of adults with the age of onset ranging from 10 to 42 years.17 It is likely genetic, with 54% of patients having a family history of similar lesions.17 The number and size of individual lesions increase with age. Histopathologic findings are similar to those seen in seborrheic keratoses.
Treatment options for seborrheic keratoses and dermatosis papulosa nigras include cryotherapy, electrodesiccation, electrodesiccation and curettage, shave biopsy and laser. In patients with darker skin, care should be taken when using invasive removal techniques, as further pigmentary alteration can occur.
Melanocytic nevi are rarely present at birth, with an incidence of 1% in newborns.18 The number of lesions increase in childhood and adolescence and reach a peak in the second and third decade.19 The average number of nevi per person in young adults ranges from 15 to 40. There is a significant correlation between skin phenotype and the number of melanocytic nevi. Patients with a fair complexion have higher mean counts of nevi than those with a darker complexion. After 50 years of age, the number of melanocytic nevi decrease, with an average of 4 per person.20 They are rarely observed in individuals older than 80.21 According to a study by Tu et al,22 the proliferative capacity and total cellularity of nevus cells decrease with age and are replaced by connective tissue elements including collagen, elastin, ground substance and fat. These changes may account for the spontaneous regression of nevi, but the exact mechanism has not yet been identified.
Graying of Hair
Graying of hair is a common phenomenon. Approximately half the population has at least 50% gray scalp hair by the end of the fifth decade,23 and virtually everyone has some degree of graying due to progressive loss of melanocytes from the hair bulb.24 Physiologically, follicular melanocytes differ slightly from epidermal melanocytes. Melanocytes in hair are lost more rapidly than in the skin. This may be due to follicular melanocytes proliferating and synthesizing melanin at maximal rates during the anagen phase of the hair cycle, whereas epidermal melanocytes are comparatively inactive throughout the life span. There may also be factors in the follicular environment that lead to hair melanocyte death earlier than surrounding epidermal pigment cells.
The age of onset of hair graying seems largely inherited. Hair graying in the 20s and early 30s is not uncommon. The average age of onset is usually the mid-30s for Caucasian patients, the late-30s for Asian patients and mid-40s for patients of African descent.23 Gray hair usually first appears at the temples and extends slowly to the vertex and the remaining area of the scalp, affecting the occiput last. Beard and body hair are usually involved later. Chest, pubic and axillary hair may retain their pigment even in old age. Scalp hair grays more rapidly than other sites because of its higher anagen-telogen ratio.25 This phenomenon is usually irreversible.
To date, all studies have confirmed that graying of hair is due to a decrease in the number of melanogenically active melanocytes in the hair follicle.26 However, the underlying mechanism responsible for hair graying is unknown. Animal models suggested hereditary factors may play an important role.27 Hair melanocytes may have their own genetically-determined biological clock. Cytotoxic actions of the intermediate melanin metabolites may be responsible for premature hair graying in genetically predisposed individuals, as suggested in the light mice model.28 The absence of α-melanocyte-stimulating hormone binding sites has been reported in senile human white hair.29 Disturbance of immune tolerance may play a role in the development of gray hair.30 Absence of melanocytes in graying hair reflects loss of the melanocyte stem cell in the hair follicle bulge, which may be due to a compromised interaction between two transcription factors, Pair box 3 (PAX3) and microphthalmia-associated transcription factor (MITF).31
Racial longitudinal melanonychia is unusual in whites (1% of population). However, in African Americans, the incidence may be as high as 77% in individuals age 20 and older with an incidence of almost 100% of those older than 50.32 It is characterized by tan, brown or black longitudinal bands along the nail plate, starting from the matrix and extending to the tip of the nail plate. In most cases, bandwidths range from 2 mm to 4 mm. Bands are more frequently located in the thumb, index finger and middle finger. The pigmentation is due to increased melanin but the number of melanocytes is normal. The number of bands and their width tend to increase with age.33
Pigmentary Changes Associated with Photoaging
All races are susceptible to photoaging. However, individuals with Fitzpatrick skin phototypes IV to VI are less susceptible, which may be due to the photo-protective role of melanin.34 In African Americans, photoaging appears primarily in lighter-skinned individuals and may not be apparent until the fifth or sixth decade of life.35 Mottled, irregular dyspigmentation is commonly found in photoaged skin of all races. The mechanism of mottled pigmentation is unknown. Ultrastructurally, irregular distribution of melanocytes with heterogenous distribution of melanosomes within keratinocytes has been observed.36 In photoaged skin, both benign hyper- and hypopigmented lesions and malignant lesions are seen.
Idiopathic Guttate Hypomelanosis
This condition is a very common, acquired hypopigmentary disorder characterized by multiple discrete asymptomatic depigmented macules approximately 2 mm to 6 mm in diameter. The lesions are circular or angular with well-defined borders and a smooth surface (Figure 2, left). The common area of distribution is the sun-exposed parts of the forearms and legs. This condition equally affects males and females, usually develops after the age of 40 or 50, and increases with age. The pathogenesis is uncertain, but the role of chronic UV exposure is probable, since most lesions occur in sun-exposed skin. It may be due to a disturbance in the production of melanocyte growth factors by keratinocytes or direct cytotoxicity from chronic exposure to UV radiation.37,38
Histopathologic examination shows a reduction in the number of melanocytes and melanin content in the basal epidermis and basket-weave hyperkeratosis with atrophy of the epidermis. Ultrastructurally, some of the melanocytes have normal melanogenic activity and contain numerous melanosomes while others contain only immature melanosomes. The melanosome content of the epidermal keratinocytes is generally decreased.39
Treatment options include cryotherapy, superficial dermabrasion, mini-grafts of normal skin implanted into the lesional skin and intralesional injection of low-concentration triamcinolone.40-43 Since idiopathic guttate hypomelanosis is not painful, many dermatologists recommend minimal intervention if the problem is mild.
Spontaneous Stellate Pseudoscars
This condition is common in elderly individuals, especially those with a fair complexion. It is characterized by a small white patch or plaque with a stellate shape on the background of diffused skin atrophy and actinic purpura (Figure 3, left). The preferential locations include the back of hands and forearms. The pathogenesis of this condition is unknown. The distribution of the lesions suggests that chronic sun exposure and repeated micro-trauma may be involved.
Histological examination of pseudoscars using specific melanin stain shows that the epidermis is normally pigmented, indicating that the white color is due to dermal abnormalities, including fibrosis, beneath the epidermis without elastic fibers.44 However, specific histochemical or ultrastructural study of the melanocytes has not yet been performed. There is no effective treatment.
Melasma is a common acquired hypermelanosis characterized by symmetric but irregular brown macules and patches. It usually involves sun-exposed areas of the skin, most commonly the face and arms.1 This condition mostly affects women and first appears during the reproductive age. It is seen in all racial groups but is more common in Hispanic and Asian patients. The exact cause of melasma remains elusive, but solar and ultraviolet exposures are the best-known etiologic factors. Exarcerbation of melasma is usually seen after a period of sun exposure; conversely, melasma gradually fades during the winter. Other factors incriminated in the pathogenesis of melasma include pregnancy, oral contraceptives, estrogen-progesterone therapies, thyroid dysfunction, cosmetics and phototoxic and antiepileptic drugs.45
Histopathology of melasma shows increased deposition of melanin in the epidermis and dermis with a normal number of melanocytes. However, the melanocytes in the hyperpigmented areas are larger, intensely stained cells with very prominent dendrites.46
First-line treatment of melasma is topical therapy, mainly fixed triple combinations (4% hydroquinone, 0.05% retinoic acid and 0.01% fluocinolone acetonide). If the patient develops side effects to the ingredients, other compounds with dual ingredients (hydroquinone plus glycolic acid) or single agents (4% hydroquinone, 0.1% retinoic acid or 20% azelaic acid) may be an alternative.47 Other treatment alternatives include chemical peels, cosmeceuticals, microdermabrasion, laser therapy and cosmetic camouflage.
Poikiloderma of Civatte
This condition is characterized by red-brown discoloration with telangiectasia. It usually appears on the front of and behind the ears and sides of the neck, but spares the shaded submental area, suggesting the role of long-term sun exposure and, possibly, the repeated use of photosensitive agents such as perfumes.48 This condition usually affects middle-aged and elderly women.
Histopathologic examination reveals a flattened epidermis with basal hyperpigmentation, solar elastosis, dilated blood vessels and sparse lymphocytic infiltration and melanophages in the dermis. This condition spreads slowly and is persistent. Vascular laser therapy can improve the telangiectatic component of this disease and depigmented agents will sometimes work on the hyperpigmentation. Use of fractional photothermolysis to treat poikiloderma of Civatte has also been described with promising results. Several treatment sessions may be required. To date, there is no single treatment that addresses the problem completely. Sunscreen should be encouraged to minimize further progression of the disease.
Solar lentigo (also known as actinic lentigo, senile lentigo, sun spots and liver spots) is one of the most common benign sun-induced lesions. The incidence of this lesion increases with age. Although they are common in older individuals, they are now seen in younger populations because of increased exposure to sun tanning. The lesions are usually light brown macules less than 5 mm in diameter. They slowly increase in size and number. Many lesions eventually coalesce to form larger patches with irregular borders. The surface of the lesions is either flat or depressed and may be split by fine wrinkles (Figure 4, above left). They may also darken after sun exposure.49 Histopathologic findings reveal elongated rete ridges and a proliferation of pigmented basaloid cells, which form buds and strands. The number of melanocytes is variably increased.50 There is an increase in endothelin-1 secreted by proliferating keratinocytes and an increase in endothelin B receptor expression in melanocytes of solar lentigine, suggesting an essential role for endothelin in the stimulation of epidermal pigmentation.51
Ink-spot lentigo (also known as reticulated black solar lentigo or sunburn lentigo), a rare variant of solar lentigo, is characterized by a dark-colored macule resembling a spot of ink with a wiry or beaded irregular outline and a reticular pattern.52 Multiple areas without pigmentary changes, or skip areas, may be seen within the center of the lesion or at the borders. This condition is usually found on sun-exposed areas of fair-skinned individuals. In contrast to solar lentigines, patients usually have only one ink-spot lentigo among an extensive number of solar lentigines. The lesion may be misinterpreted as melanoma because of its dark color, irregular border and limited number. However, the histologic finding is distinctive and allows for the diagnosis of this benign lesion.
Available treatment modalities include a topical bleaching agent, chemical peels, cryotherapy and pigmented-specific laser (eg, Q-switched Nd:YAG, Q-switched ruby and Alexandrite).53
Spreading Pigmented Actinic Keratosis
This rare variant of actinic keratosis, known as spreading pigmented actinic keratosis, was introduced by James et al in 1978.54 The majority of patients described by the authors were older than 60 and predominately female.55 Spreading pigmented actinic keratoses are characterized by brown-gray pigmented lesions larger than 1 cm that spread laterally, resulting in large areas of extensive actinic damage with varying degrees of brown or gray pigmentation. The surface is smooth or slightly scaly. The lesions are primarily located on sun-exposed areas, with 70% involving the head and neck.56 The cause of the increased melanin is unknown. This condition may be difficult to distinguish from other brown pigmented lesions on sun-exposed skin like lentigo maligna, solar lentigo and early seborrheic keratosis.
Histopathologic examination reveals the typical features of actinic keratosis, with increased melanin in the epidermal basal layer and numerous melanophages in the papillary dermis. The number and morphology of epidermal melanocytes are normal. There is a paucity of data regarding the malignant potential of this condition, although progression to pigmented squamous cell carcinoma has been described.54,57 Destructive therapies such as cryotherapy are recommended.
Pigmented Basal Cell Carcinoma
Pigmented basal cell carcinoma is reported to represent 6.7% to 9% of all basal cell carcinomas.58 This particular form is most frequently seen in individuals with dark skin.59,60 Clinically, they appear as a hyperpigmented, translucent papules or nodules that may be ulcerated (Figure 5).
Histopathologic findings reveal melanocytes that contain numerous melanin granules in the cytoplasm and dendrites scattered in the epithelial tumor cells with many melanophages in the dermal stroma surrounding the lesion. However, there are few transferred melanosomes in the epithelial tumor cells.61 The recommended treatment modality for basal cell carcinoma is surgery.62
Lentigo Maligna and Lentigo Maligna Melanoma
The incidence of malignant melanoma is highest in lightly-pigmented Caucasians as compared to Hispanics, Asians and African Americans. The mean age of diagnosis is relatively young — 52 years. The clinical features and pattern of sun exposure varies between the types (sustained in lentigo maligna vs. intermittent in superficial spreading). Superficial spreading melanoma tends to occur at sites of intermittent, intense sun exposure (eg, on trunk in males and legs and back in females). Lentigo maligna melanoma is more prevalent on the chronically sun-damaged skin of the head, neck and arms.
Lentigo maligna, the in situ lesion of malignant melanoma, is characterized by an asymmetrical area of homogenous pigmentation ranging from dark brown to black with irregular border. The size is usually large, up to 1 cm to 3 cm in diameter. It grows slowly, over a period of 5 to 20 years. It is most commonly occurs on the sun-exposed areas of elderly patients. The incidence increases progressively with age, with an average age of onset of 65 years. It occurs slightly more often in women.63
Histologically, lentigo maligna shows an increased number of atypical melanocytes in the basal layers of the epidermis. The atypical melanocytes are arranged in solitary units or small nests beyond the clinical margin and extend into the follicular outer root sheath and eccrine duct. There are numerous melanophages in the upper dermis. The signs of sun-damaged skin, including epidermal atrophy and solar elastosis, are usually observed.
Lentigo maligna melanoma is characterized by the development of dermal invasion of lentigo maligna. It has been estimated that 5% of lentigo maligna progress to invasive melanoma.64 It usually presents as a dark papule or nodule arising on a pigmented patch with marked variation in color and topography. The prognosis of lentigo maligna melanoma correlates with depth of invasion or thickness. Treatment of choice for lentigo maligna and lentigo maligna melanoma is wide local excision with the appropriate margin according to the thickness.65
As patients continue to live longer, dermatologists are likely to continue to see a greater number of patients with pigmentary changes due to aging. In the skin pigmentary system, there are many changes associated with age. Some of these changes are inevitable, such as chronological aging, but some conditions, such as photoaging, are preventable. Pigmentary changes have long been considered a cosmetic problem. However, there are some conditions that are not just cosmetic; they can also be premalignant and malignant. Dermatologists should be aware of these changes and function as key players in prevention, diagnosis and treatment.
Dr. Vachiramon is with the Division of Dermatology at Ramathibodi Hospital of Mahidol University in Bangkok, Thailand.