Chapter 057. Photosensitivity and Other Reactions to Light (Part 3) doc

Chronic Effects of Sun Exposure: Nonmalignant The clinical features of photodamaged sun-exposed skin consist of wrinkling, blotchiness, and telangiectasia and a roughened, irregular, "w

Chapter 057 Photosensitivity and Other Reactions to Light

(Part 3)

Vitamin D Photochemistry

Cutaneous exposure to UV-B causes photolysis of epidermal 7-dehydrocholesterol converting it to pre-vitamin D3, which then undergoes a temperature-dependent isomerization to form the stable hormone vitamin D3 This compound then diffuses to the dermal vasculature and circulates systemically where it is converted to the functional hormone 1,25-dihydroxyvitamin

D3[1,25(OH)2D3] Vitamin D metabolites from the circulation or those produced in the skin itself can augment epidermal differentiation signaling Controversy exists regarding the importance of sun exposure in vitamin D homeostasis At present, it

is important to emphasize that the use of sunscreens does not substantially diminish vitamin D levels Since aging also substantially decreases the ability of

human skin to photocatalytically produce vitamin D3, the widespread use of sunscreens that filter out UV-B has led to concern that vitamin D deficiency may become a significant clinical problem in the elderly

Chronic Effects of Sun Exposure: Nonmalignant

The clinical features of photodamaged sun-exposed skin consist of wrinkling, blotchiness, and telangiectasia and a roughened, irregular, "weather-beaten" leathery appearance Whether this photoaging represents accelerated chronologic aging or a separate and distinct process is not clear

Within chronically sun-exposed epidermis, there is thickening (acanthosis) and morphologic heterogeneity within the basal cell layer Higher but irregular melanosome content may be present in some keratinocytes, indicating prolonged residence of the cells in the basal cell layer These structural changes may help to explain the leathery texture and the blotchy discoloration of sun-damaged skin

UV-A is important in the pathogenesis of photoaging in human skin, and ROS are likely involved The dermis and its connective tissue matrix are the major site for sun-associated chronic damage, manifest as solar elastosis, a massive increase in thickened irregular masses of abnormal elastic fibers Collagen fibers are also abnormally clumped in the deeper dermis of sun-damaged skin The chromophore(s), the action spectra, and the specific biochemical events orchestrating these changes are only partially understood, although UV-A seems

to be primarily involved Chronologically aged, sun-protected skin and photoaged skin share important molecular features including connective tissue damage and elevated matrix metalloproteinases (MMPs) MMPs are enzymes involved in the degradation of the extracellular matrix, and UV-A induces MMP-1 and MMP-3 mRNA expression, leading to enhanced collagen breakdown In addition, UV-A reduces type I procollagen mRNA expression

Chronic Effects of Sun Exposure: Malignant

One of the major known consequences of chronic skin exposure to sunlight

is nonmelanoma skin cancer The two types of nonmelanoma skin cancer are basal

cell carcinoma (BCC) and squamous cell carcinoma (SCC; Chap 83) There are

three major steps for cancer induction: initiation, promotion, and progression

Exposure of human skin to sunlight results in initiation, a step whereby structural

(mutagenic) changes in DNA evoke an irreversible alteration in the target cell

(keratinocyte) that begins the tumorigenic process Exposure to a tumor initiator

such as UV-B is believed to be a necessary but not sufficient step in the malignant process, since initiated skin cells not exposed to tumor promoters do not generally

develop tumors The second stage in tumor development is promotion, a multistep

process whereby chronic exposure to sunlight evokes epigenetic changes that culminate in the clonal expansion of initiated cells and cause the development,

over many years, of premalignant growths known as actinic keratoses, a minority

of which may progress to form skin cancer Based on extensive studies it seems

clear that UV-B is a complete carcinogen, meaning that it can act as both a tumor

initiator and a promoter

The third and final step in the malignant process is malignant conversion of

benign precursors into malignant lesions, a process thought to require additional genetic alterations in already transformed cells Skin carcinogenesis is thought to

be caused by the accumulation of mutations in the tumor-suppressor gene p53 as a

result of UV-induced DNA damage Indeed both human and murine UV-induced

skin cancers have unique p53 mutations (C →T and CC →TT transitions) that are

present in the majority of these lesions Studies have shown that sunscreens can

substantially reduce the frequency of these signature mutations in p53 and can dramatically inhibit the induction of tumors The p53 mutations are present in

sun-exposed normal human skin, in actinic keratoses, and in nonmelanoma skin cancers including BCC and SCC

BCCs also manifest mutations in the tumor-suppressor gene known as

patched, which results in activation of hedgehog signaling, and enhanced activity

of smoothened, which in turn causes downstream activation of transcription

factors that augment cell proliferation Thus, these tumors can manifest mutations

in both p53 and in patched

Sun exposure causes nonmelanoma cancers and melanoma of the skin, although the evidence is far more direct for its role in nonmelanoma (BCC and

SCC) than in melanoma Approximately 80% of nonmelanoma skin cancers develop on exposed body areas, including the face, the neck, and the hands Major risk factors include male sex, childhood sun exposures, older age, fair skin, and residence at latitudes closer to the equator Whites of darker complexions (e.g., Hispanics) have one-tenth the risk of developing such cancers compared to fair-skinned individuals Blacks are at substantially reduced risk for all forms of skin cancer More than 1.3 million individuals in the United States develop nonmelanoma skin cancer annually, and the lifetime risk for a fair-skinned individual to develop such a neoplasm is estimated at ~15% A consensus exists that the incidence of nonmelanoma skin cancer in the population is increasing at the rate of 2–3% per year, for unknown reasons One potential explanation is the widespread use of indoor tanning It is estimated that 30 million people tan indoors

in the United States annually, including >2 million adolescents

The relationship of sun exposure to melanoma development is less clear-cut, but suggestive evidence supports an association The strongest risk factors for melanoma include positive family history for melanoma, multiple dysplastic nevi, and prior melanoma Melanomas occasionally develop by the teenage years, indicating that the latent period for tumor growth is less than that of nonmelanoma skin cancer Melanomas are among the most rapidly increasing of all human malignancies (Chap 83) Epidemiologic studies of immigrant populations of similar ethnic stock indicate that individuals born in one area or who migrate to

the same locale before age 10 have higher age-specific melanoma rates than individuals arriving later It is thus reasonable to conclude that life in a sunny climate from birth or early childhood increases the risk of melanoma In general, risk does not correlate with cumulative sun exposure but may relate to the duration and extent of exposure in childhood Epidemiologic studies have shown that indoor tanning is a risk factor for melanoma

Meta-analysis of 17 case-control studies in patients with melanoma concluded that the protective effect of sunscreens against this type of tumor could not be substantiated, but this is likely due to failure to control for confounding factors such as sunscreen stability and frequency of application Since no prospective studies are available to address this issue, it seems reasonable to recommend that patients at risk for melanoma utilize photoprotection such as sun avoidance, high sun protective factor (SPF) sunscreens, and protective clothing