Dermatology for Pediatric and Adolescent Gynecology Indoor Tanning, Skin Cancer and the Young Female Patient: A Review of the Literature Blake Friedman BA, Joseph C. English III MD *, Laura K. Ferris MD, PhD Department of Dermatology, University of Pittsburgh, Pittsburgh, PA

a b s t r a c t Young, non-Hispanic white females represent the population most likely to use indoor tanning facilities. This population may be at increased risk of skin cancer as recent meta-analyses support a strong association between cutaneous malignancy and indoor tanning. Public perception of the purported health benefits of indoor tanning may be partially to blame for the popularity of tanning salons as a desire to prepare skin prior to sun exposure is among the most commonly cited motivations for indoor tanning. Improving education and counseling to address misconceptions regarding tanning safety will require the participation of healthcare providers for both physical and psychological screenings as well as for information dissemination. This review presents the association between tanning bed use and skin cancer, biological effects of UV radiation exposure, UV burden associated with tanning devices, public perception of tanning, demographic and psychological profile of indoor tanners, and current legislation regulating tanning bed use. Key Words: Indoor tanning, skin cancer, melanoma, ultraviolet radiation, tanning legislation, patient education

Introduction

Melanoma is the most prevalent cancer among young adults 25-29 years of age and the second most prevalent cancer in young adults 15-29 years of age.1 Among younger adults, melanoma incidence is higher in females, with a female:male incidence ratio of 1.70:1 among young adults aged 15-29 years.1,2 Additionally, the sharpest rise in melanoma incidence is seen among young women.3,4 A recent report found a 2.9% annual increase in the incidence of melanoma in young females aged 10-14 years and a 1.9% annual increase in females aged 15-19 years from 1973 to 2009.5 An additional study examining melanoma incidence in females aged 0-30 years over a 15-year period noted a 2.5% annual increase from 1992-2006.6 This upward trend in melanoma incidence in young women is thought to be in part attributable to a relatively new source of UV radiation: indoor tanning equipment.7 It has been proposed that this alarming rise in melanoma may be the result of improved screening and surveillance techniques, which would result in an expected increase in the number of diagnosed thinner tumors with minimal metastatic potential.8e10 However, recent findings showed an increased incidence of fatal, thick melanomas (O4 mm), suggesting that improved surveillance and screening does not account for the rise in melanoma.10 Others have noted that tanning bed users are more likely to sunbathe, making it difficult to link the rise in melanoma incidence to tanning bed use.11 However, recent studies strongly suggest that tanning device use is an independent and significant risk factor in the development of The authors indicate no conflicts of interest. * Address correspondence to: Joseph C. English III, MD, Department of Dermatology, University of Pittsburgh, 200 Lothrop St, Suite 3880 Presby South Tower, Pittsburgh, PA 15213; fax: (412) 647-4137 E-mail address: [email protected] (J.C. English III).

melanoma.12 In fact, an editorial published in the British Journal of Dermatology determined that approximately 25% of the rise in melanoma was attributable to tanning bed use.13 Other UV-induced skin cancers, including basal cell carcinoma and squamous cell carcinoma of the skin, are also increased among tanners. Although less deadly than melanoma, these skin cancers are far more prevalent and their treatment results in financial burden to the health care system. The indoor tanning industry has evolved into a multibillion dollar business, with more tanning salons than Starbucks or McDonald's in 166 large cities in the US.4,14e16 The growth of the tanning industry since the opening of the first commercial tanning salon in 1970 largely parallels the reported increase in melanoma incidence and recent metaanalyses showed an association between indoor tanning device use and cutaneous malignant melanoma.17 Despite evidence pointing to the hazards of tanning device use for cosmetic purposes, few regulations are in place to improve the safety of potential tanning salon patrons.3 Increasing regulations and altering physician practice to include education and counseling for indoor tanners is imperative. Risks Associated with Indoor Tanning Devices

In 2006, the International Agency for Research on Cancer (IARC) published a systematic review of the association between cutaneous malignant melanoma and the use of tanning devices. The review showed a positive association between melanoma and ever-use of sunbeds with an increased risk when first exposure to tanning beds occurred prior to the age of 35.18 The IARC findings on the hazards of UV exposure prompted the re-categorization of tanning devices as Group 1 carcinogens.7 In 2012, Boniol et al

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Table 1 Summary of Relative Risks Found in Recent Meta-analyses on Cutaneous Melanoma and Sunbed Use17,18 Sunbed Use

Number of Studies in IARC Meta-Analysis

Summary Relative Risk (95% CI)

Number of Studies in Boniol Meta-Analysis

Summary Relative Risk (95% CI)

Ever use First use in youth (!35 y) High use

19 7 NR

1.15 (1.00-1.31) 1.75 (1.35-2.26) NR

27 13 14

1.20 (1.08-1.34) 1.87 (1.41-2.48) 1.42 (1.15-1.74)

NR, not reported

updated the IARC review to include more recent studies. Incorporating new data on the association between tanning beds and melanoma was essential, because relative risks increased over the period of time directly following the publication of the IARC systematic review (2005-2011).17 See Table 1. The characteristic lag time between UV exposure and melanoma development might account for the increase in summary relative risks seen during this period.15 Incidence of melanoma may have been underreported by earlier studies included in the IARC analysis that did not allow for a long post-exposure latency period given the relatively recent emergence of the indoor tanning trend.15,18 The 2012 systematic review largely corroborated the findings of the IARC analysis, showing a positive association between melanoma and ever-use of sunbeds (summary relative risk, 1.20; 95%CI, 1.08-1.34) with no indication of publication bias.17 Evaluation of 13 studies showed an increase in relative risk of melanoma when first exposure to tanning device occurred prior to age 35 (summary relative risk, 1.87; 95%CI, 1.41-2.48).17 In contrast to the IARC review, the updated 2012 review found evidence of a dose response with each session of tanning device use increasing risk for melanoma by 1.8% (95%CI, 0-3.8).14,17 At the time of the IARC review, there was insufficient published data to perform a meta-regression analysis, which may have prevented the discovery of a dose response relationship.17 The updated Boniol et al review included data from more recent studies that sought to elucidate the dose response relationship, allowing for a more comprehensive evaluation of the effect of incremental increases in number of tanning sessions on melanoma risk.17 Studies investigating the association between other UV-induced skin cancers and use of indoor tanning devices have shown a similar trend.19,20 A large cohort study showed a positive association between squamous cell carcinoma (SCC) incidence and ever-use of indoor tanning devices at ages ranging from 10-49 years (relative risk, 1.93; 95%CI, 1.27-2.95).19 This corroborates findings of a recent meta-analysis that showed a strong association between SCC and ever-use of indoor tanning facilities (summary relative risk, 1.67; 95%CI, 1.29-2.17) with increased relative risk when first exposure to tanning beds occurred prior to the age of 25 (relative risk, 2.02; 95%CI, 0.70-5.86).21 This same meta-analysis found an association between ever-use of tanning beds and risk of basal cell carcinoma (BCC) with a summary relative risk of 1.29 (95%CI, 1.08-1.53) and increased risk associated with early exposure to tanning devices (relative risk, 1.40; 95%CI, 1.29-1.52).21 An additional case-control study examining early-onset BCC in a population aged 40 years or younger found a 69% increased risk for development of early-onset BCC associated with ever-use of

indoor tanning devices (odds ratio (OR), 1.69; 95%CI, 1.152.48), with a greater association seen in women (OR, 2.14; 95%CI, 1.31-3.47) and a dose-dependent increase in risk observed.20 Carcinogen Status of Ultraviolet Radiation

UV radiation is classified into 3 categories based on wavelength: UVA (O315-400 nm), UVB (O280-315 nm), and UVC (100-280 nm).18 Before 1990, it was believed that UVB radiation was the only part of the UV spectrum implicated in carcinogenesis and that UVA-induced tans were safer than those caused by UVB.17,18 This perception of UVA began to shift in 1992 when the IARC classified UVB and UVA radiation along with sunbeds as Group 2A carcinogens (“probably carcinogenic to humans”).22 In 2002, the National Toxicology Program in the USA published their 10th report on carcinogens in which they labeled UVA radiation as “known to be a human carcinogen.”23 Most recently, the IARC re-classified indoor tanning devices and the full spectrum of UV radiation as Group I carcinogens (“carcinogenic to humans”).24 Biological Effects of Ultraviolet Radiation Exposure DNA Damage

The depth of UV penetration in skin is wavelengthdependent with UVB wavelengths penetrating into the epidermis and papillary epidermis and UVA wavelengths penetrating through the epidermis and dermis.25 (Fig. 1) The wavelength of light associated with UVB rays is well absorbed by heterocyclic DNA bases.26 This allows UVB rays to directly affect DNA by inducing the formation of cyclobutane pyrimidine dimers that lead to C/T and CC/TT mutations.26 While UVA rays are not absorbed directly by DNA bases, a recent study showed that cyclobutane pyrimidine dimers were a primary mutation present in skin lesions induced in UVA irradiated skin.27 Thus, although UVB and UVA exert their mutagenic effects through different mechanisms, they both result in the formation of a similar mutation. Repair and removal of DNA damaged via UVA radiation occurs at a significantly lower rate than removal of DNA damaged via UVB radiation27 (Fig. 2). p53 Mutation

Skin exposure to UV radiation leads to an accumulation of p53 protein in skin cell nuclei that can be indicative of early events in tumorigenesis.28 The p53 tumor suppressor plays a number of important roles in the prevention of

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Fig. 1. The UV radiation spectrum can be subdivided into 3 parts: UVC (100-280 nm), UVB (280-315 nm) and UVA (315-400 nm). UVC rays have the highest energy and can cause the most damage to human DNA. However, the vast majority of UVC rays are absorbed by the ozone layer. Additionally, UVC rays are not emitted by modern day tanning devices. UVA and UVB rays penetrate the atmosphere to reach human skin, albeit to different degrees. Higher energy UVB rays are partially blocked by clouds and account for approximately 5% of the solar UV spectrum. UVA rays account for the remaining 95% of the solar UV spectrum and are capable of penetrating more deeply into the dermis. The proportion of UVA and UVB rays emitted by tanning devices varies.

photocarcinogenesis, including (1) stimulation of apoptosis, (2) arrestment of the cell cycle, and (3) enhancement of UVinduced DNA damage repair.29 While p53 aids in the repair and removal of UV-induced DNA damage, p53 present in the skin is vulnerable to the same dipyrimidine mutation it is capable of regulating.15 In fact, mutations in p53 tumor suppressor gene are the most common known UV-induced

mutations.30 Therefore, UV radiation has dual carcinogenic potential as it both induces DNA mutations throughout the genome and eliminates the protective effects of the primary tumor suppressor.31,32 The p53 tumor suppressor also plays an integral role in the tanning pathway. DNA damage in keratinocytes initiates tanning by activating p53, leading to the up-regulation of pro-opiomelanocortin (POMC) gene expression.33 The resulting polypeptide is cleaved into multiple products, including alpha-melanocyte stimulating hormone, a hormone that stimulates melanocytes via the melanocortin 1 receptor (MC1R).34 Loss-of-function polymorphisms in MC1R as seen in red-haired individuals classified as phototype I (always burns, does not tan) result in burning without tanning and a loss of MC1R DNA repair function.35,36 Thus, while UV-induced DNA damage can proceed in the absence of tanning, tanning cannot occur without the initiation of the tanning pathway by DNA damage.15 (Fig. 3) Immunosuppression

In addition to its mutagenic effects, UV radiation also facilitates carcinogenesis via immunosuppression.37e40 While the exact pathomechanism responsible for UVinduced immunosuppression remains unknown, multiple factors have been studied. UV radiation has been shown to impair antigen presenting cell (APC) function, generate immunosuppressive cytokines and prostaglandins, induce CD4þCD25þ T regulatory cells and promote the migration of immature epidermal Langerhans cells to the draining lymph nodes.40e44 Fig. 2. Both UVA and UVB exposure lead to the formation of cyclobutane pyrimidine dimers through different mechanisms. UVB directly damages DNA, whereas UVA damages DNA indirectly through chromophores. DNA damaged via UVA exposure is repaired and removed at a significantly lower rate than DNA damaged via UVB radiation. Unrepaired DNA damage as a result of UV exposure can lead to photocarcinogenesis.

UV Burden

Indoor tanning devices emit levels of UV radiation that greatly exceed the levels found in natural sunlight in order

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Fig. 3. UV radiation from tanning beds causes DNA damage in the nucleus of keratinocytes, resulting in the activation of P53. P53 activation leads to the up-regulation of POMC gene expression. Post-translational modification of POMC gene products results in the production of b-endorphin and melanocyte-stimulating hormone (MSH). b-endorphin, an endogenous ligand of the m-opioid receptor, has been implicated in tanning addiction behaviors. Melanocyte-stimulating hormone acts on the melanocortin-1 receptor (MC1R), which is found on melanocytes residing at the basal layer of the epidermis. Stimulation of MC1R induces pigment production and tanning. In individuals with a loss of function polymorphism in MC1R, such as red-haired individuals classified as phototype I, burning without tanning occurs.

to promote faster tanning.45 In a study examining UV output at 62 tanning facilities in North Carolina, the average UVA radiation level was 192 W/m2 or 4 times the amount of solar UVA radiation at noon in Washington, DC, during the summer.46 Additionally, the UVB radiation level was twice that of solar UVB radiation at noon.46 Powerful sunbeds can provide UV exposure equivalent to 10-15 times that of midday sunlight in the Mediterranean.47 The ratio of UVA:UVB found in the solar spectrum also differs from that found in tanning beds, which varies considerably among devices.45 The proportion of UVB radiation in tanning devices can range from 0.5%-4%.18 The solar UV spectrum consists of approximately 95% UVA and 5% UVB.48 In tanning devices with a lower proportion of UVB radiation than found in natural sunlight, exposure to higher levels of UVA in a condensed timeframe without appreciable burning is possible. Therefore, persons who utilize tanning devices may be subjected to higher levels of DNA damaging UVA radiation without visual cues to indicate risk.7

responsible manner is rooted in a misunderstanding of the tanning processda misconception that is exacerbated by information disseminated by tanning salons. A recent investigation of tanning facilities revealed that only 7% of salons informed patrons of the potential dangers of UV exposure via indoor tanning, 90% stated that there was no associated risk and 78% reported the purported health benefits.51 (Fig. 4) Many of the facilities investigated specifically cited health benefits for young, fair-skinned girls.51 In contrast to information distributed by tanning salons, several studies have concluded that a “safe tan” is not possible as DNA damage is required to initiate tanning and the DNA damage intermediate that promotes the tanning pathway is identical to the intermediate seen in carcinogenesis.15,39,52 Additionally, studies suggest that exposure to suberythemal doses of UV radiation confers virtually no protection against future DNA damage.15,53e55 Therefore, the DNA damage incurred during the tanning process outweighs any photoprotective benefit.56 Vitamin D

Public Perception of Tanning Safe Tan

Among the most commonly cited motivations for the use of indoor tanning devices are the attainment of a “safe tan” and skin preparation prior to sun exposure.49,50 The public perception that tanning can be achieved in a safe and

UV exposure stimulates the conversion of 7dehydrocholesterol to pre-vitamin D which can be processed into active vitamin D in the liver and kidney.15 Proponents of indoor tanning assert that tanning provides substantial health benefits by increasing levels of vitamin D through this process and cite concerns that reduced levels of vitamin D may be associated with increased incidence of cancer.12,52 However

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Self-Treatment for Medical Conditions

Fig. 4. Data from an investigative report conducted in 2012 by the U.S. House of Representatives Committee on Energy and Commerce that assessed accuracy of information on health risks provided by tanning salons. Minority staff members posing as fair-skinned adolescent girls contacted 300 tanning salons and inquired about health risks associated with tanning. Accurate information on health risks was presented by 7% of tanning salons contacted, whereas 90% of tanning salons stated that there was no risk associated with indoor tanning. The remaining 3% of tanning salons did not provide clear answers.

there are mixed reports regarding the association between levels of vitamin D and cancer prevention with some studies suggesting that vitamin D may increase cancer risk.57e59 Additionally, UV radiation exposure offers a poor method of inducing vitamin D production due to the numerous variables involved, including degree of skin exposure, UV spectrum of indoor tanning devices, and skin pigmentation.7,60 Importantly, proponents of the indoor tanning industry who cite the vitamin D associated benefits of UV exposure fail to acknowledge that the population most likely to utilize indoor tanning devicesdyoung, non-Hispanic white females who often tan poorlydis also the population least likely to be deficient in vitamin D and most at risk for photodamage.45,60 Potential benefits of vitamin D can be obtained through options with less variability like vitamin D supplements. When used along with intermittent serum vitamin D level monitoring, vitamin D supplements provide a more effective method of raising vitamin D levels than UV exposure.7 Public relations campaigns and websites created by proponents of the tanning industry focus on the benefits of vitamin D production and the lack of concrete evidence linking melanoma to UV exposure.15,61 The tanning industry is not alone in the propagation of information extolling the benefits of tanning and rejecting the potential hazards of UV exposure. A 2004 study published by the American Journal of Clinical Nutrition not only lauded tanning devices as an effective means of obtaining vitamin D, but also cited the use of sunscreen as a reason for vitamin D deficiency, stating that sunscreen with a sun protective factor of 8 or more diminishes UV-induced vitamin D production by greater than 95%.62,63 This same study pointed to the lack of a causal link between UV exposure and melanoma, stating that the true risk factors for melanoma are red hair, number of moles, and number of lifetime sunburns.62,64 Disconcertingly, to substantiate their claim that UV exposure does not serve as a true risk factor for melanoma, the authors cite an article published by the Journal of the National Cancer Institute which recommends the avoidance of UV exposure through refraining from solarium use.64

Tanning industry supported websites suggest that indoor tanning devices can be used for self-treatment of skin conditions such as psoriasis, eczema, and vitiligo.61 While phototherapy is integral to the treatment of several dermatological disorders, the prescribed use of UV devices for the treatment of skin conditions differs from nonprescribed tanning device use in several significant ways.52 Importantly, during phototherapy, a physician who has assessed the risk-benefit ratio of UV exposure prior to prescribing phototreatment closely monitors and evaluates patients for acute and chronic effects.65 Additionally, UV devices utilized in phototherapy are subject to constant and rigorous testing to ensure that they are in accordance with prescribed treatment protocol and that they minimize risks associated with UV light devices.52,66 The main phototherapy treatment used today involves narrow-band UVB that emits UV radiation at 311 nm, a wavelength shown to provide maximum therapeutic benefits while minimizing risk of erythema.66,67 In contrast to the strict controls and safety precautions in place for phototherapy devices, many tanning facilities fail to meet safety guidelines and have variable levels of UVA and UVB.46,51,60,68 Additionally, tanning bed operators often lack knowledge regarding the risks associated with UV exposure.68,69 Affected Population Demographics

The tanning industry in the United States is flourishing with approximately 30 million Americans visiting tanning salons to achieve tanned skin each year.7 In the Youth Risk Behavior Survey conducted by the CDC in 2012, 13.3% of US high school students reported using an indoor tanning device over the previous year.70 The prevalence of tanning device use was higher in US high-school-aged females (20.9%).70 A 2014 meta-analysis on international prevalence of indoor tanning found that 14% (95%CI, 11.5-24.0) of adults, 43.1% (95%CI, 21.7-64.5) of university students and 18.3% (95%CI, 12.6-24.0) of adolescents had used a tanning device in the past year.71 While estimates of usage vary, several studies suggest that the predominant population utilizing indoor tanning facilities is young, non-Hispanic white women.3,71e73 Usage of indoor tanning devices by this population increases with age, with a significantly higher rate of indoor tanning among girls aged 17 or older than among girls younger than 17.72 This population is in line with the target population of tanning industry marketing campaigns that feature advertisements promoting tanning for prom, back-to-school, and homecoming.51 As recent meta-analyses have indicated a relationship between early exposure to tanning devices and incidence of melanoma, the prevalence of young women using indoor tanning devices is particularly troubling. Phototype

Indoor tanning device users are more likely to be fair skinned, or classified as phototype I/II (burns easily, tans

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poorly) than phototype III/IV (burns minimally, tans easily), than non-users.74 Individuals with naturally darker skin types have a higher photoprotection factor and a resultant lower rate of photocarcinogenesis.75 Photoprotection provided by a constitutively darker skin type with higher melanin content results from defense against DNA damage.29,76 However, although UV-induced DNA damage is less severe in darker-skinned individuals than lighter-skinned individuals, DNA damage is appreciable in all skin types post-UV exposure.76 While fair-skinned individuals exposed to repetitive physiologically relevant doses of UV radiation do see an increase in pigmentation, they do not see the accompanying increase in cell apoptosis appreciable in darker-skinned individuals upon UV exposure.29 This is particularly important as the process of UV-induced apoptosis is thought to be integral to the prevention of DNA photodamage in darker-skinned individuals.29,77 Thus, UV-induced increases in skin pigmentation in fair-skinned individuals only provides modest photoprotection as compared to the natural protection provided by constitutive pigmentation.29 Importantly, while both UVA and UVB exposure can result in a visible increase in skin pigmentation, only UVB exposure results in increased melanin production and modestly increased photoprotection.78 This information is especially relevant given both the prevalence of UVA-rich tanning devices and the belief that tanning beds provide an increase in photoprotection via the acquisition of a “base tan.”49,75 Psychological and Behavioral Profile

Indoor tanning device use has been associated with a number of harmful health-related behaviors in adolescents, including binge drinking, tobacco use, recreational drug use, unintended pregnancy, sexually transmitted infections, and unhealthy dieting.72 Additionally, obsessivecompulsive symptoms, anxiety, and non-prescription steroid use have been associated with indoor tanning device use in young men.72,79 Future research should investigate effective behavioral interventions to reduce tanning in at risk youths. Several studies have shown evidence for tanning addiction in individuals who use indoor tanning facilities.7,80 Tanning addiction may be the result of endogenous opioid release upon UV exposure.33,81 b-endorphin, an endogenous ligand of the m-opioid receptor, is a POMC cleavage product.3 The effects of endogenous b-endorphin are comparable to those of exogenous opiates.3 A recent randomized control trial examining the effects of an opioid antagonist, naltrexone, in young adults who utilized indoor tanning devices found evidence of opiate withdrawal that was not present in infrequent tanners or tanners who received non-UV light exposure.82 Assessment of behaviors associated with problematic tanning found that early age of first tanning, and being female were associated with meeting the criteria for tanning addiction.83 An additional study examining university students found a strong association between tanning dependence and positive screenings on indicators of both obsessive compulsive and body dysmorphic disorder.84 The overall prevalence of

tanning dependence differs by population and method of measurement with the highest rates seen in college-aged indoor tanners (22%-45%).85 Federal and State Regulations FDA Classification

The Food and Drug Administration (FDA) designates medical devices as belonging to 1 of 3 categories: Class I, Class II, and Class III.86 Class I devices are regarded as the most benign and are thought to pose minimal potential for injury or damage.52 These devices are subject to general controls such as FDA notification and appropriate labeling and branding prior to device marketing.52 Until recently, indoor tanning beds were categorized as Class I devices with 501(k) exemption, meaning premarketing FDA notification proving device safety and efficacy was not required.52 Tongue depressors, hand held surgical instruments, and elastic bandages are examples of Class I medical devices.52 In 2010, the FDA advisory panel unanimously recommended increasing the classification of tanning beds.87 An official proposal to raise indoor tanning devices to Class II medical devices was put forward in May 2013.87 Class II devices include those devices that necessitate special controls in addition to general controls.52 Special controls include post-market surveillance, patient registries, and distribution of educational literature.52 The proposal was adopted on May 29, 2014, leading to the official reclassification of tanning beds as Class II devices.88 Tanning facilities are now required to display warning labels on tanning devices and promotional materials and will no longer be exempt from premarket notification.88 Other devices included in the Class II category are X-ray devices and UV lamps used for phototherapy by dermatologists.52 Federal Legislation

Under the Affordable Care Act, tanning salons are required to add a 10% federal excise tax on top of the cost of all tanning services.3 Importantly, tanning services as outlined by the ACA do not include sunless tanning options such as spray tanning treatments.3 Over the next 10 years, the so-called tanning tax is predicted to raise approximately 2.7 billion dollars.3 Currently there is no federal legislation regulating the use of indoor tanning facilities by minors. State Legislation

State legislation regulating indoor tanning facility use largely centers on prohibiting or limiting access to minors. In 2011, California signed the first state law prohibiting patrons less than 18 years of age from accessing tanning facilities.3,89 A similar law was passed in Vermont less than a year later in May 2012.3,89 Currently, 9 states prohibit the use of tanning facilities by minors under 18 years of age, including California, Delaware, Illinois, Louisiana, Minnesota, Nevada, Oregon, Texas, and Vermont.89 In addition, 41 states and the District of Columbia have regulations in place, including requirements for parental accompaniment or

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consent.89 Several states have introduced new legislation in an attempt to increase restrictions on tanning bed use by minors.89 The American Academy of Pediatrics' 2011 policy statement on ultraviolet radiation serves as a call to action, encouraging pediatricians to advocate for legislation prohibiting tanning salon access to children under the age of 18.90 While increased regulations governing the use of tanning salons are imperative, improved enforcement of current and future regulations will be critical. A recent study demonstrated that the presence of state legislation regulating indoor tanning facility access was not associated with actual use, suggesting that noncompliance and lack of enforcement may render state-imposed regulations ineffective.91 Legislation Abroad

Anti-tanning legislation banning all indoor tanning devices for cosmetic use was enacted in Brazil in 2009.3 In 2012, New South Wales, a state in Australia, announced a total ban of all tanning devices by 2014.3 In addition to laws prohibiting the use and sale of all tanning devices, laws banning minors access to tanning facilities exist in France, Germany, Austria, and the United Kingdom.3 Moving Forward Patient Education

Due to the misinformation surrounding indoor tanning and UV-related health benefits, patient education regarding sun protection, the risks of UV exposure, and alternative means of obtaining vitamin D is necessary. A 2007 survey found that only 15% of participants had discussed indoor tanning with their physician.92 This low percentage is noteworthy as results from the same survey suggested that physicians were among the most trusted resources of information.92 Additional studies examining the most effective means of modifying tanning habits found that emphasis on the aesthetic advantages of sun protection (ie, preservation of youthful appearance and attractiveness) might be more effective than education on melanoma risk alone.93,94 The Role of Primary Health Care Providers

Primary health care providers, as the principal touch point for young patients, are in a unique position to counsel individuals aged 10-24 years about reducing UV radiation exposure in line with recommendations from the U.S. Preventive Services Task Force (USPSTF).95 Tanning salon avoidance should be discussed during annual well-child and well-adolescent visits, ideally before the onset of tanning behaviors (age 13-14).3 As counseling patients on avoidance of tanning beds received a Grade B recommendation rating from the USPSTF, it is considered a fully reimbursable and covered service under the Affordable Care Act.96 In order to effectively counsel patients, health care providers should attempt to better understand tanning behaviors of family members as maternal tanning behaviors

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may be strongly predictive of youth tanning bed use. A recent study showed that youths accompanied by their mothers on their first indoor tanning experience had a significantly increased risk of becoming frequent indoor tanners.97 A separate survey-based study examining parental knowledge of indoor tanning found that the majority of participants believed tans obtained in a tanning facility were protective against future sunburns.98 Health care providers should consider educating parents on the risks of indoor tanning both to prevent parental involvement in the initiation of youth tanning behavior and to encourage parental contribution to discussions on tanning bed avoidance.98 To initiate conversations on tanning, health care providers should ask open-ended questions such as, “How does going to the tanning salon make you feel?,” to ascertain tanning motivators.3 Patient motivations for tanning should inform patient education and counseling.3 Table 2 outlines tanning motivators and suggestions for primary care health care providers regarding patient counseling. While recent research indicates tanning interventions can be effective in adolescents, it is imperative that future studies examine best methods of discussing tanning salon use with adolescents and their guardians. As indoor tanners may demonstrate signs of addiction, health care providers may need to approach tanning as they would other potentially hazardous addictive behaviors and include screening questions in the history-taking process.3,95 To ensure these discussions occur, patient forms should include a question on indoor tanning use.3 Electronic records should also be modified to include a prompt to discuss tanning salon use.3 Physical Examination Findings on Skin

Health care providers should perform thorough skin checks of the trunk, including the breasts and genital areas, during annual examinations as skin that is normally concealed from sunlight may receive significant UV exposure in individuals who frequent indoor tanning facilities.99,100 The commonly cited mnemonic used in the clinical diagnosis of skin cancer is ABCDE, which stands for asymmetry in 2 or more axes, irregular borders, color variegation, diameter of 6 mm or greater, and evolution.101 Melanoma has also been associated with the “ugly duckling” sign, a mole that differs significantly in appearance from other moles on the patient's body.102 Gynecological and Breast Examination Considerations

Gynecological specialists should be aware of the potential for melanoma to metastasize to the breast and gynecological organs.103e106 While caution should be taken when examining patients with a history of skin cancer, it should be noted that secondary breast tumors frequently serve as the first sign of disease in patients with breast metastases from melanoma.103,107 During patient examination, health care providers should thoroughly examine the upper outer quadrants of the breasts as metastases occur more frequently in these regions due to the local

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Table 2 Recommendations for appropriate patient counseling based on patient motivators for tanning as described by Balk et al.3 Type of Tanning Behavior Event tanning Regular tanning

Motivation for Tanning Preparation for an occasion; mainly esthetic Relaxation, mood improvement

Suggested Substitution Spray tanning, tanning lotion Running, dancing, aerobic activities

Patient Education Appearance-based, focused on premature skin aging, skin-cancer risk* Appearance-based, focused on premature skin aging, skin cancer risk

* Appearance based counseling may be particularly effective in “event tanners” and adolescent women.

abundance of glandular tissue and high blood supply.108 In cases with metastatic involvement of the gynecological organs, the ovaries serve as the most commonly affected site.105 However, uterine metastases from melanoma have been reported.104,105 While patients with uterine involvement are often asymptomatic, patients may present with abnormal uterine bleeding when the endometrium is involved.104 Gynecological specialists should remember that abnormal uterine bleeding can be the first sign of metastatic melanoma affecting the endometrium. Due to the high metastatic potential of melanoma and the alarming rise in melanoma incidence in young women, vigilant screenings for both primary and secondary melanoma by gynecological specialists is essential. Political Action

Federal legislation mirroring legislation abroad should be considered due to the strong association between melanoma and indoor tanning device use. Additionally, since evidence suggests poor enforcement of already passed legislation, measures need to be taken to ensure compliance, including frequent inspections and increased issuance of citations.3 References 1. Herzog C, Pappo A, Bondy M, et al: Malignant melanoma. In: Bleyer A, O'Leary M, Barr R, Ries LAG, editors. Cancer epidemiology in older adolescents and young adults 15-29 years of age, including SEER incidence and survival 1975-2000. Bethesda, National Cancer Institute, 2006, pp 53e63 2. Little EG, Eide MJ: Update on the current state of melanoma incidence. Dermatol Clin 2012; 30:355 3. Balk SJ, Fisher DE, Geller AC: Teens and indoor tanning: a cancer prevention opportunity for pediatricians. Pediatrics 2013; 131:772 4. Purdue MP, Freeman LE, Anderson WF, et al: Recent trends in incidence of cutaneous melanoma among US Caucasian young adults. J Invest Dermatol 2008; 128:2905 5. Wong JR, Harris JK, Rodriguez-Galindo C, et al: Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics 2013; 131:846 6. Senerchia AA, Ribeiro KB, Rodriguez-Galindo C: Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study. Pediatr Blood Cancer 2014; 61:211 7. Fisher DE, James WD: Indoor tanningeScience, behavior, and policy. N Engl J Med 2010; 363:901 8. Welch HG, Woloshin S, Schwartz LM: Skin biopsy rates and incidence of melanoma: population based ecological study. BMJ 2005; 331:481 9. Swerlick RA, Chen S: The melanoma epidemic. Is increased surveillance the solution or the problem? Arch Dermatol 1996; 132:881 10. Linos E, Swetter SM, Cockburn MG, et al: Increasing burden of melanoma in the United States. J Invest Dermatol 2009; 129:1666 11. Ting W, Schultz K, Cac NN, et al: Tanning bed exposure increases the risk of malignant melanoma. Int J Dermatol 2007; 46:1253 12. Mogensen M, Jemec GB: The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice. Cancer Manag Res 2010; 2:277 13. Diffey B: Sunbeds, beauty and melanoma. Br J Dermatol 2007; 157:215 14. Lazovich D, Vogel RI, Berwick M, et al: Indoor tanning and risk of melanoma: a case-control study in a highly exposed population. Cancer Epidemiol Biomarkers Prev 2010; 19:1557 15. Schulman JM, Fisher DE: Indoor ultraviolet tanning and skin cancer: health risks and opportunities. Curr Opin Oncol 2009; 21:144

16. Hoerster KD, Garrow RL, Mayer JA, et al: Density of indoor tanning facilities in 116 large U.S. cities. Am J Prev Med 2009; 36:243 17. Boniol M, Autier P, Boyle P, et al: Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 2012; 345:e4757 18. IARC Working Group on artificial ultraviolet (UV) light and skin cancer: The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. Int J Cancer 2007; 120:1116 19. Veierød MB, Couto E, Lund E, et al: Host characteristics, sun exposure, indoor tanning and risk of squamous cell carcinoma of the skin. Int J Cancer 2013; 135:413 20. Ferrucci LM, Cartmel B, Molinaro AM, et al: Indoor tanning and risk of early-onset basal cell carcinoma. J Am Acad Dermatol 2012; 67:552 21. Wehner MR, Shive ML, Chren MM, et al: Indoor tanning and non-melanoma skin cancer: systematic review and meta-analysis. BMJ 2012; 345:e5909 22. International Agency for Research on Cancer: Solar and ultraviolet radiation. IARC Monogr Eval Carcinog Risks Hum 1992; 55:1 23. National Toxicology Program: 10th Report on Carcinogens: substances profiles. Triangle Park, NC, US Department of Health and Human Services, Public Health Service, 2002 24. El Ghissassi F, Baan R, Straif K, et al: WHO International Agency for Research on Cancer Monograph Working Group: A review of human carcinogensepart D: radiation. Lancet Oncol 2009; 10:751 25. O'Leary RE, Diehl J, Levins PC: Update on tanning: More risks, fewer benefits. J Am Acad Dermatol 2014; 70:562 26. Ravanat JL, Douki T, Cadet J: Direct and indirect effects of UV radiation on DNA and its components. J Photochem Photobiol B 2001; 63:88 27. Mouret S, Baudouin C, Charveron M, et al: Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation. Proc Natl Acad Sci U S A 2006; 103:13765 28. Benjamin CL, Ananthaswamy HN: p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol 2007; 224:241 29. Yamaguchi Y, Coelho SG, Zmudzka BZ, et al: Cyclobutane pyrimidine dimer formation and p53 production in human skin after repeated UV irradiation. Exp Dermatol 2008; 17:916 30. Ananthaswamy HN, Kanjilal S: Oncogenes and tumor suppressor genes in photocarcinogenesis. Photochem Photobiol 1996; 63:428 31. Brash DE, Rudolph JA, Simon JA, et al: A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991; 88:10124 32. Brash DE, Ziegler A, Jonason AS, et al: Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc 1996; 1:136 33. Cui R, Widlund HR, Feige E, et al: Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 2007; 128:853 34. D'Orazio JA, Nobuhisa T, Cui R, et al: Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 2006; 443:340 35. Valverde P, Healy E, Jackson I, et al: Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995; 11:328 36. Abdel-Malek ZA, Ruwe A, Kavanagh-Starner R, et al: alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. Pigment Cell Melanoma Res 2009; 22:635 37. Fisher MS, Kripke ML: Suppressor T lymphocytes control the development of primary skin cancers in ultraviolet-irradiated mice. Science 1982; 216:1133 38. Halliday GM, Byrne SN, Damian DL: Ultraviolet A radiation: its role in immunosuppression and carcinogenesis. Semin Cutan Med Surg 2011; 30:214 39. Halliday GM, Lyons JG: Inflammatory doses of UV may not be necessary for skin carcinogenesis. Photochem Photobiol 2008; 84:272 40. Ullrich SE, Byrne SN: The immunologic revolution: photoimmunology. J Invest Dermatol 2012; 132:896 41. Greene MI, Sy MS, Kripke M, et al: Impairment of antigen-presenting cell function by ultraviolet radiation. Proc Natl Acad Sci U S A 1979; 76:6591 42. Byrne SN, Halliday GM: B cells activated in lymph nodes in response to ultraviolet irradiation or by interleukin-10 inhibit dendritic cell induction of immunity. J Invest Dermatol 2005; 124:570 43. Ullrich SE: Mechanisms underlying UV-induced immune suppression. Mutat Res 2005; 571:185 44. Schwarz T: 25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells. Photochem Photobiol 2008; 84:10 45. Gilchrest BA: Sun exposure and vitamin D sufficiency. Am J Clin Nutr 2008; 88:570S

B. Friedman et al. / J Pediatr Adolesc Gynecol 28 (2015) 275e283 46. Hornung RL, Magee KH, Lee WJ, et al: Tanning facility use: are we exceeding Food and Drug Administration limits? J Am Acad Dermatol 2003; 49:655 47. Gerber B, Mathys P, Moser M, et al: Ultraviolet emission spectra of sunbeds. Photochem Photobiol 2002; 76:664 48. Miller SA, Hamilton SL, Wester UG, et al: An analysis of UVA emissions from sunlamps and the potential importance for melanoma. Photochem Photobiol 1998; 68:63 49. Autier P: Perspectives in melanoma prevention: the case of sunbeds. Eur J Cancer 2004; 40:2367 50. Oliver H, Ferguson J, Moseley H: Quantitative risk assessment of sunbeds: impact of new high power lamps. Br J Dermatol 2007; 157:350 51. U.S. House of Representatives Committee on Energy and Commerce - Minority Staff: False and Misleading Health Information Provided to Teens by the Indoor Tanning Industry. Available: http://www.democrats.energycommerce.house.gov/ sites/default/files/documents/False-Health-Info-by-Indoor-Tanning-Industry2012-2-1.pdf. Accessed February 22, 2014. 52. Lim HW, James WD, Rigel DS, et al: Adverse effects of ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan. J Am Acad Dermatol 2011; 64:893 53. Sheehan JM, Cragg N, Chadwick CA, et al: Repeated ultraviolet exposure affords the same protection against DNA photodamage and erythema in human skin types II and IV but is associated with faster DNA repair in skin type IV. J Invest Dermatol 2002; 118:825 54. Bykov VJ, Marcusson JA, Hemminki K: Protective effects of tanning on cutaneous DNA damage in situ. Dermatology 2001; 202:22 55. Levine JA, Sorace M, Spencer J, et al: The indoor UV tanning industry: a review of skin cancer risk, health benefit claims, and regulation. J Am Acad Dermatol 2005; 53:1038 56. Eller MS, Gilchrest BA: Tanning as part of the eukaryotic SOS response. Pigment Cell Res 2000; 13:94 57. Reddy KK, Gilchrest BA: What is all this commotion about vitamin D? J Invest Dermatol 2010; 130:321 58. Stolzenberg-Solomon RZ, Vieth R, Azad A, et al: A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 2006; 66:10213 59. Davis CD: Vitamin D and cancer: current dilemmas and future research needs. Am J Clin Nutr 2008; 88:565S 60. Woo DK, Eide MJ: Tanning beds, skin cancer, and vitamin D: An examination of the scientific evidence and public health implications. Dermatol Ther 2010; 23:61 61. Smart Tan. Available: http://www.tanningtruth.com. Accessed February 25, 2014 62. Tangpricha V, Turner A, Spina C, et al: Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Am J Clin Nutr 2004; 80:1645 63. Matsuoka LY, Ide L, Wortsman J, et al: Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab 1987; 64:1165 €rn M, et al: A prospective study of 64. Veierød MB, Weiderpass E, Tho pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst 2003; 95:1530 65. Menter A, Korman NJ, Elmets CA, et al: Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol 2010; 62:114 66. Walters IB, Burack LH, Coven TR, et al: Suberythemogenic narrow-band UVB is markedly more effective than conventional UVB in treatment of psoriasis vulgaris. J Am Acad Dermatol 1999; 40:893 67. Calzavara-Pinton P: Narrow band UVB (311 nm) phototherapy and PUVA photochemotherapy: a combination. J Am Acad Dermatol 1998; 38(5 Pt 1):687 68. Culley CA, Mayer JA, Eckhardt L, et al: Compliance with federal and state legislation by indoor tanning facilities in San Diego. J Am Acad Dermatol 2001; 44:53 69. Kwon HT, Mayer JA, Walker KK, et al: Promotion of frequent tanning sessions by indoor tanning facilities: two studies. J Am Acad Dermatol 2002; 46:700 70. Eaton DK, Kann L, Kinchen S, et al: Centers for Disease Control and Prevention (CDC): Youth risk behavior surveillance - United States, 2011. MMWR Surveill Summ 2012; 61:1 71. Wehner MR, Chren MM, Nameth D, et al: International prevalence of indoor tanning: a systematic review and meta-analysis. JAMA Dermatol 2014; 150: 390 72. Guy GP Jr, Berkowitz Z, Tai E, et al: Indoor tanning among high school students in the United States, 2009 and 2011. JAMA Dermatol 2014; 150:501 73. Watson M, Holman DM, Fox KA, et al: Preventing skin cancer through reduction of indoor tanning: current evidence. Am J Prev Med 2013; 44:682 74. Ezzedine K, Malvy D, Mauger E, et al: Artificial and natural ultraviolet radiation exposure: beliefs and behaviour of 7200 French adults. J Eur Acad Dermatol Venereol 2008; 22:186 75. Coelho SG, Hearing VJ: UVA tanning is involved in the increased incidence of skin cancers in fair-skinned young women. Pigment Cell Melanoma Res 2010; 23:57 76. Tadokoro T, Kobayashi N, Zmudzka BZ, et al: UV-induced DNA damage and melanin content in human skin differing in racial/ethnic origin. FASEB J 2003; 17:1177

283

77. Lee CH, Wu SB, Hong CH, et al: Molecular mechanisms of UV-induced apoptosis and its effects on skin residential cells: The implication in UV-based phototherapy. Int J Mol Sci 2013; 14:6414 78. Wolber R, Schlenz K, Wakamatsu K, et al: Pigmentation effects of solar-simulated radiation as compared with UVA and UVB radiation. Pigment Cell Melanoma Res 2008; 21:487 79. Mosher CE, Danoff-Burg S: Indoor tanning, mental health, and substance use among college students: the significance of gender. J Health Psychol 2010; 15: 819 80. Nolan BV, Taylor SL, Liguori A, et al: Tanning as an addictive behavior: a literature review. Photodermatol Photoimmunol Photomed 2009; 25:12 81. Zeller S, Lazovich D, Forster J, et al: Do adolescent indoor tanners exhibit dependency? J Am Acad Dermatol 2006; 54:589 82. Kaur M, Liguori A, Lang W, et al: Induction of withdrawal-like symptoms in a small randomized, controlled trial of opioid blockade in frequent tanners. J Am Acad Dermatol 2006; 54:709 83. Harrington CR, Beswick TC, Leitenberger J, et al: Addictive-like behaviours to ultraviolet light among frequent indoor tanners. Clin Exp Dermatol 2011; 36: 33 84. Ashrafioun L, Bonar EE: Tanning addiction and psychopathology: Further evaluation of anxiety disorders and substance abuse. J Am Acad Dermatol 2014; 70:473 85. Heckman CJ, Darlow S, Kloss JD, et al: Measurement of tanning dependence. J Eur Acad Dermatol Venereol 2014; 28:1179 86. US Food and Drug Administration: Overview of device regulation. Available: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ default.htm. Accessed February 26, 2014. 87. Skin Cancer Foundation: FDA Proposes Raising Tanning Beds to a Higher Risk Classification Available: http://www.skincancer.org/publications/sun-and-skinnews/fall-2013-30-3/tanning. Accessed February 27, 2014. 88. US Food and Drug Administration: FDA to require warnings on sunlamp products. Available: http://www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm399222.htm. Accessed June 30, 2014. 89. National Conference of State Legislatures: Indoor Tanning Restrictions for Minors - A State-by-State Comparison. Available: http://www.ncsl.org/ research/health/indoor-tanning-restrictions.aspx. Accessed November 4, 2014. 90. Balk SJ: Council on Environmental Health, Section on Dermatology: Ultraviolet radiation: a hazard to children and adolescents. Pediatrics 2011; 127:e791 91. Cokkinides V, Weinstock M, Lazovich D, et al: Indoor tanning use among adolescents in the US, 1998 to 2004. Cancer 2009; 115:190 92. Robinson JK, Kim J, Rosenbaum S, et al: Indoor tanning knowledge, attitudes, and behavior among young adults from 1988-2007. Arch Dermatol 2008; 144: 484 93. Hillhouse J, Turrisi R, Stapleton J, et al: A randomized controlled trial of an appearance-focused intervention to prevent skin cancer. Cancer 2008; 113: 3257 94. Stapleton J, Turrisi R, Hillhouse J, et al: A comparison of the efficacy of an appearance-focused skin cancer intervention within indoor tanner subgroups identified by latent profile analysis. J Behav Med 2010; 33:181 95. Ladizinski B, Lee KC, Ladizinski R, et al: Indoor tanning amongst young adults: time to stop sleeping on the banning of sunbeds. J Gen Intern Med 2013; 28:1551 96. The Henry J Kaiser Family Foundation. Summary of new health reform Law. Available: http://www.kff.org/healthreform/upload/8061.pdf. Accessed June 30, 2014. 97. Baker MK, Hillhouse JJ, Liu X: The effect of initial indoor tanning with mother on current tanning patterns. Arch Dermatol 2010; 146:1427 98. Magee KH, Poorsattar S, Seidel KD, et al: Tanning device usage: what are parents thinking? Pediatr Dermatol 2007; 24:216 99. Christenson LJ, Borrowman TA, Vachon CM, et al: Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 2005; 294:681 100. Weir HK, Marrett LD, Cokkinides V, et al: Melanoma in adolescents and young adults (ages 15-39 years): United States, 1999-2006. J Am Acad Dermatol 2011; 65:S38 101. Robinson JK, Ortiz S: Use of photographs illustrating ABCDE criteria in skin self-examination. Arch Dermatol 2009; 145:332 102. Pizzichetta MA, Stanganelli I, Bono R, et al: Italian Melanoma Intergroup: Dermoscopic features of difficult melanoma. Dermatol Surg 2007; 33:91 103. Bassi F, Gatti G, Mauri E, et al: Breast metastases from cutaneous malignant melanoma. Breast 2004; 13:533 104. Berker B, Sertcelik A, Kaygusuz G, et al: Abnormal uterine bleeding as a presenting sign of metastasis to the endometrium in a patient with a history of cutaneous malignant melanoma. Gynecol Oncol 2004; 93:252 105. Fambrini M, Andersson KL, Buccoliero AM, et al: Late solitary metastasis of cutaneous malignant melanoma presenting as abnormal uterine bleeding. J Obstet Gynaecol Res 2008; 34(4 Pt 2):731 106. Bakelaar RT, Soper JT, Lutman CV: Cutaneous malignant melanoma metastatic to a uterine leiomyoma: a case report. J Reprod Med 2008; 53:697 107. Al Samaraee A, Khout H, Barakat T, et al: Breast metastasis from a melanoma. Ochsner J 2012; 12:149 108. Majeski J: Bilateral breast masses as initial presentation of widely metastatic melanoma. J Surg Oncol 1999; 72:175