Epidemiology and Screening of Pigmented Lesions

1	Epidemiology and Screening of Pigmented Lesions Veronica J. Shi and Jonathan Scott Leventhal

INTRODUCTION

Melanoma is a malignant tumor of melanocytes that typically develop in the skin and may, in rare cases, develop in the mouth, intestines, or eyes. The National Cancer Institute tabulates statistics in the Surveillance, Epidemiologic, and End Results (SEER) Program, and according to most recent data, melanoma is the sixth most common invasive cancer in the United States (1). Over the past several decades, the incidence of cutaneous melanoma has increased dramatically among White populations worldwide (2). In addition, melanoma is the most rapidly increasing cancer in Whites; rates have tripled over the past 30 years in the United States and in Central Europe (2). Epidemiologic studies have helped define genetic and environmental risk factors that may contribute to the development of melanoma. This chapter highlights the incidence, patient demographics, and mortality rates of melanoma and reviews the environmental and genetic risk factors. The recommendation practices for screening pigmented lesions will then be summarized.

EPIDEMIOLOGY

Rising Incidence and Patient Demographics

Over the past several decades, the incidence of melanoma has increased significantly. It has been estimated that rates have increased from 6 cases/100,000 in the 1970s to 21.6/100,000 in 2015 in the United States (Figure 1.1) (1–3). According to the most recent SEER database, there was an estimated 73,870 new cases of melanoma of the skin in the United States in 2015 and an estimated 9,940 deaths from melanoma (1). According to the American Cancer Society (ACS), the overall lifetime risk of developing melanoma is about 1 in 40 for Whites, 1 in 1,000 for Blacks, and 1 in 200 for Hispanics (3). The continuous rise in melanoma has been demonstrated in countries predominantly inhabited by Whites, consistent with the higher likelihood of developing melanoma in lighter-skinned individuals (1–3). Australia and New Zealand have the highest reported incidence rates of melanoma in the world, followed by the southern United States (2–4). The incidence is generally lower in European countries (2). The southern Mediterranean countries with darker skin types report lower rates than the northern Scandinavian countries with lighter skin types (2).

Figure 1.1 New cases of melanoma and deaths from 1975 to 2013. SEER 9 Incidence & U.S. Mortality 1975 to 2013, all races, both sexes. Rates are age-adjusted.

Source: Adapted from Ref. (1). SEER Cancer Statistics Factsheets. Melanoma of the Skin. Bethesda, MD: National Cancer Institute. www.seer.cancer.gov/statfacts/html/melan.html

In contrast to nonmelanoma skin cancers, cutaneous melanoma is commonly diagnosed at an earlier age. The median age is approximately 55 to 64 years of age in the United States (1); however, thicker melanomas are found at higher rates in individuals older than 60 years of age (5). Possible explanations for thicker tumors in older patients include decreased vision, lower likelihood of performing self-examinations, increased seborrheic keratoses complicating the observation of new or changing pigmented lesions, and lower inclination to report changes in color or texture of skin lesions until symptoms of bleeding or ulceration develop (5). Older patients are also more likely to develop melanoma in sites of chronic sun exposure, in particular the head and neck (2,5).

Gender analysis demonstrates that the ratio of male to female incidence may vary based on the country. In countries with higher incidence such as Australia and the United States, melanoma was found more commonly in men (1–3). In countries with lower incidence such as the United Kingdom, a higher ratio of women patients may be found (6). Recent studies suggest that in the United States, melanoma incidence is rising more steeply among women than men in the younger age groups (<50 years old) (7). This has been attributed to increased tanning bed habits (7). The anatomic site of melanoma varies according to gender, with 55% of tumors in men localized on the trunk (with 39% on the back) whereas in women, 42% are localized on the lower extremities (2).

Whether the increased incidence of melanoma represents a true epidemic remains an area of controversy. Some studies attribute the rising incidence to environmental risk factors with ozone depletion and carcinogenesis from ultraviolet (UV) exposure, while other studies suggest that better screening practices and earlier detection of thinner and less biologically aggressive tumors may contribute to the rising incidence (2,8–10). Others postulate that the rise in melanoma is not fully explained by improved screening practices as low socioeconomic groups with less routine surveillance have increased rates as well, and tumors of both low and high thickness may be on the rise (8,10). Regardless of whether a true epidemic exists, cutaneous melanoma has become one of the most common malignancies in the United States and there is a growing need to identify individuals most at risk.

Mortality Rates

Melanoma is one of the most deadly skin cancers; prior estimates suggest that one person in the United States dies every hour from the disease (11). On a global scale, mortality rates increased throughout the 1980s in most European countries as well as in North America, Australia, and New Zealand, then peaked in the late 1980s (1,2,10,11). Different studies report varying trends in mortality, but most recent SEER data suggests that mortality has stabilized over the past few years in the United States (2008–2012) (1,10). The favorable mortality trends may be related to changing patterns of sun exposure and sunburn in younger generations as well as earlier detection of thinner and less biologically aggressive melanomas (2,10).

The mortality risk in individuals with melanoma depends on a number of factors, including age, race, and gender. In general, studies have demonstrated that women and patients younger than 65 years of age have significantly longer survival rates compared with men and older patients, respectively (5). Some studies suggest that mortality from melanoma continues to increase in men aged 65 and older, whereas both men and women under 65 years of age demonstrate decreased mortality rates (8). While incidence rates for melanoma are lower among Hispanic and Black populations compared with non-Hispanic White populations in the United States, these minority groups are more likely to have melanomas that metastasize and have poorer outcomes (8,12). This may be explained by less access to health prevention education and practices in these populations (8,12).

Regarding prognosis, the Breslow depth or vertical tumor thickness is the single most important local prognostic factor in cutaneous melanoma (2,13–15). Tumors that are detected earlier will likely have lower Breslow depth and a favorable prognosis (>95% long-term survival in tumors <1 mm) (15). Unfortunately, patients with deep primary tumors or tumors that metastasize to regional lymph nodes frequently develop distant metastases. The overall 5-year survival for patients with visceral disease is less than 5% (15).

The status of an individual’s immune system is another important clinical factor that affects mortality. Individuals with weakened immune systems, such as those infected with HIV or with AIDS as well as organ transplant recipients on immunosuppressive therapy, have been shown to be at greater risk of dying from melanoma (3).

Risk Factors for Melanoma

UV exposure

Epidemiologic studies have consistently demonstrated that sun exposure is the major environmental risk factor for developing cutaneous melanoma (16). The UV spectrum includes UVA (95% of midday solar radiation reaching Earth’s surface), UVB (5% of solar radiation), and UVC (largely removed by stratospheric ozone layer) (17). While the entire UV spectrum is classified as carcinogenic to humans (18), UVA as well as UVB have both been shown to induce melanoma in animal models (17,18). Mouse models have shown UVA (320–400 nm) to cause oxidative DNA damage within melanocytes and UVB (280–320 nm) to cause direct UV DNA damage (17,18). UVB rays, which are the major cause of sunburn, have a more intense effect in equatorial regions where there is a higher incidence of melanoma. UVA rays, with a longer wavelength, penetrate to the deeper layers of skin and likely play a greater role in melanoma incidence from tanning beds, where fluorescent bulbs emit mostly UVA rays with smaller doses of UVB rays (7).

Meta-analyses of epidemiologic studies show that the type of sun exposure that increases melanoma risk is the intermittent pattern of sun exposure (short, intense exposure through leisurely outdoor activities and holidays in sunny climates) (16). Furthermore, 80% of melanomas develop in regions that receive intermittent sun exposure (2). In contrast, lentigo maligna melanoma, which is more common in elderly patients, develops from chronic cumulative sun-damaged skin on the head and neck (2). In addition, sunburns in childhood and adolescence, in particular, were shown to elevate the risk for melanoma development (2,19–21). The proportion of melanoma attributed to sun exposure has been estimated to be as high as 65% to 90% (9,22).

In addition to solar exposure, there is a growing trend of indoor tanning bed use in the United States. Approximately 20% of all female high school students have reported tanning indoors, and 30% of White female high school students have tanned indoors (23). These trends might explain the steeper increase in melanoma rates in the United States among younger women compared with men (7). A recent population-based case-control study was conducted in Minnesota on 681 patients diagnosed with melanoma between 2004 and 2007. The study demonstrated that women younger than 30 years were six times more likely to be in the melanoma group than in the control group if they tanned indoors (7). In 2009, the International Agency of Research on Cancer (IARC) classified indoor tanning devices as carcinogenic to humans (18). In the United States, many states regulate the use of tanning facilities, precluding minors under age 18 from tanning. The FDA has also increased their regulation of the tanning industry with certification requirements and recommended exposure safety limits. Hopefully, the combination of efforts by the legislature and FDA as well as enhanced patient counseling by providers will reduce the incidence of melanoma from UV exposure.

The use of sunscreen to reduce the risk of melanoma has been widely studied. While there are varying results, one seminal randomized controlled trial of regular sunscreen use among 1,621 people aged 25 to 75 in Queensland, Australia, demonstrated a 50% reduction in melanoma incidence, particularly invasive melanomas, at a 10-year follow-up (24). The ACS recommends counseling patients on use of sunscreen as well as sun protective behavior. This includes avoiding sunlight during midday hours (10 a.m.–4 p.m.), when the sun’s rays are strongest; using sunscreen (SPF 30 or higher) with frequent reapplication; and covering the skin with clothing, hats, and sunglasses (3).

Nevi and pigmentation factors

Nevi are common benign melanocytic collections that have been closely studied in association with the development of melanoma. The number of melanocytic nevi has been identified as the most important inherent risk factor for cutaneous melanoma (15,25). Studies have demonstrated that with growing numbers of melanocytic nevi, the melanoma risk increases almost linearly (15). A meta-analysis showed that individuals with more than 100 normal nevi had an approximately seven times greater risk of melanoma than those with less than 15 nevi (25). In addition, atypical nevi are associated with increased melanoma risk such that one atypical nevus confers a 1.6 times greater risk of melanoma and five or more atypical nevi confer a 10-fold increased risk (25). Childhood sun exposure and sunburn are also significantly associated with increased number of nevi and atypical nevi (15,21). While prior histologic studies reported a wide range of melanomas associated with underlying melanocytic nevi (4%–72%), a recent prospective study of high-risk patients (i.e., multiple nevi or atypical nevi, atypical mole syndrome, or familial atypical mole syndrome) demonstrated 52.4% of primary melanomas were associated with melanocytic nevi (26). The authors suggested that compared with individuals at risk for de novo melanoma, patients with multiple acquired nevi appear to be at higher risk for nevus-associated melanomas (26).

Other pigmentation characteristics have been associated with the development of melanoma including skin type, ability to tan, hair color, eye color, and freckling. In general, individuals with more pigmentation of their eyes, skin, and hair have a lower risk of developing melanoma (4,27). Skin reaction to the sun is also a predictor of melanoma risk, as well as increasing number of sunburns (27). A pooled analysis of 10 case-control studies demonstrated that both fair skin type and a high degree of freckling were associated with a two-fold increased risk of developing melanoma, independent of each other, the hair color, and number of nevi (27). The relative risks for developing melanoma in individuals with light brown, blonde, and red hair were 1.49, 1.84, and 2.38, respectively, compared with individuals with black or dark brown hair (27). Individuals with blue eyes had a risk of 1.55 times, compared with individuals with brown eyes (27). It is important for clinicians to recognize the phenotypic traits that place individuals at risk for developing melanoma and counsel these individuals on screening and prevention.

Genetic risk factors

An estimated 5% to 12% of all melanomas are thought to be caused by inherited, high-penetrance, germline mutations (28). Hereditary melanoma, also known as familial atypical multiple mole melanoma (FAMMM) syndrome, is an autosomal dominant group of disorders characterized by hundreds of dysplastic nevi on individuals with an increased risk of melanoma (28). A number of genes have been implicated including the tumor suppressors cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) and the telomerase complex proteins telomerase reverse transcriptase gene (TERT) and protection of telomeres 1 (POT1) (28). The most common mutation is in CDKN2A, which encodes p16 and p14, which are genes that have a regulatory role on the cell cycle through the retinoblastoma protein and p53 pathways, respectively. Inherited mutations in the CDKN2A, CDK4, POT1, and TERT confer a 60% to 90% lifetime risk of melanoma (28). In addition, individuals with mutations in CDKN2A/p16 may have up to a 20% risk for pancreatic cancer (28). Other associated malignancies with familial melanoma syndrome include nervous system tumors or ovarian, renal, bladder, breast, and lung cancers (28).

There are many other syndromes associated with increased melanoma risk including BAP1 cancer syndrome (cutaneous and uveal melanoma, renal cancer, and mesothelioma), Li–Fraumeni syndrome (tumor protein 53 [TP53] gene with associated cutaneous and uveal melanoma; breast, bone, soft tissue, and central nervous system tumors; and leukemia), xeroderma pigmentosum (XPC, XPD, and XPA genes, with associated cutaneous melanoma and other nonmelanoma skin cancers), phosphatase and tensin homolog [PTEN] hamartoma tumor syndromes (PTEN gene, associated cutaneous melanoma, trichilemmomas, hamartomas, and breast, colorectal, thyroid, kidney, and endometrial cancer), and hereditary breast cancer and ovarian cancer syndromes (breast cancer 1 or 2 [BRCA 1/2] genes, cutaneous, and uveal melanoma) (28). There is also an increased susceptibility to melanoma and renal cell carcinoma with mutations in melanogenesis-associated transcription factor (MITF) gene (28).

Through continued research, it is likely that more genes will be discovered to play a role in melanocytic growth and proliferation, as well as the development into melanoma. Currently, some notable somatic mutations that may confer increased melanoma risk include melanocortin-1 receptor (MC1R) gene, neuroblastoma RAS viral oncogene homolog (NRAS) (nodular subtypes), BRAF (superficial spreading melanoma, intermittent sun exposure sites), KIT mutations (mucosal, acral, and sun-damaged sites), and G protein subunit alpha Q (GNAQ) and G protein subunit alpha 11 (GNA11) (uveal and central nervous system [CNS] melanomas) (4,29).

Patients with strong family histories of melanoma should be offered genetic counseling. The risk of melanoma is at least double for first-degree relatives of individuals with melanoma and five-fold higher if two first-degree relatives or more are affected (30). Importantly, regardless of whether genetic tests identify a gene mutation in these individuals, they should be counseled on their increased risk and sun prevention practices as well as the recommendation for full-body skin examinations. Genetics and genomics will continue to be important factors in treating melanoma on an individualized basis and may offer prognostic information. Furthermore, understanding the biological pathways and genetics involved in melanoma development will hopefully translate into new therapeutic targets.

SCREENING OF PIGMENTED LESIONS

Screening Recommendations

In the United States, there are presently no national screening guidelines for melanoma despite evidence that melanoma is a potentially lethal cancer with rising incidence rates. A screening program entails a balance of benefits and harms. The major benefit is the detection of a potentially lethal tumor, at a thinner, earlier stage, which may translate into a survival benefit. The potential harms include misdiagnosis, overdiagnosis, false reassurance, anxiety, and cost, as well as complications of skin biopsy and treatments. A comprehensive review of clinical studies and randomized trials are necessary to demonstrate whether screening results in a survival benefit.

The United States Preventive Services Task Force (USPSTF), in 2001, reviewed clinical data for skin cancer screening. They determined that there was insufficient evidence to recommend for or against routine screening with whole-body skin examination for the early detection of cutaneous melanoma, basal cell cancer, or squamous cell cancer in the adult general population (31). The USPSTF based their decision on a lack of high-quality evidence (i.e., randomized trials) demonstrating improved health outcomes, as well as the limited information about the utility of adequate examinations by primary care providers (31). An update by the USPSTF in 2009 re-examined these two issues, but found no new evidence on the effectiveness of skin examination in reducing the morbidity or mortality from melanoma (32). While there remains a paucity of randomized trials, other high-impact studies have explored the utility of melanoma screening.

Evidence for Earlier Detection

Many previous studies have consistently shown that melanoma screening programs identify tumors that are thinner on average than those found during routine care. A screening by dermatologists participating in the American Academy of Dermatology’s skin cancer screening program from 1985 to 1999 demonstrated detection of a higher percentage of thin melanomas less than 1.5 mm (10% of cases), compared with 2% of cases reported in the SEER registry (p < 0.001) (33). In another study of 816 patients with melanoma, lesions identified by physicians were thinner than those identified by nonphysicians (0.68 mm vs. 0.90 mm) (34). Furthermore, patients who performed skin self-examinations had significantly thinner melanomas than those who did not (0.77 mm vs. 0.95 mm) (34). Similar findings have been replicated in more recent papers (35,36). These studies support the role of whole-body skin examinations, either by a physician or by the patient, in detecting early staged, thinner melanomas.

The effect of earlier detection of thinner tumors by screening programs on disease morbidity and mortality has been extensively studied. According to recent SEER data, while the incidence rates of melanoma have increased, the overall mortality has not changed substantially, suggesting that detection of less biologically aggressive tumors may not significantly impact overall mortality rates (32). One analysis of 650 cases from the Connecticut Tumor Registry demonstrated that there was no statistically significant association between a physician screening examination or a patient self-examination and the risk of death from melanoma (37). However, a community-based program conducted at Lawrence Livermore National Laboratory in California found the incidence of thicker melanomas (>0.75 mm) significantly decreased from 22.1 to 4.62 cases/100,000 persons years after screening was initiated, with no melanoma deaths occurring during the screening period (expected number of deaths was calculated to be 3.39 deaths) (38). Another study demonstrated individuals who did not perform skin self-examination had a continuous increased risk of death from melanoma for approximately 20 years after diagnosis, whereas melanoma deaths in skin self-examiners plateaued before 10 years after diagnosis (39). While these results did not reach statistical significance (p = 0.32), individuals who were more aware of changes in their skin were significantly less likely to die of their melanoma over 16 years of follow-up (39). Such studies support the role of educating patients on self-examinations.

The largest population-based skin cancer screening project in the world took place in Germany in 2003. The Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany (SCREEN) project provided whole-body skin examination to 360,288 patients (40). Melanoma mortality rates were compared before and after screening in the same location, as well as to matched nonscreened areas elsewhere in Germany. Interim analysis in 2008 demonstrated a 47% and 49% reduction in mortality in men and women, respectively (40). The majority (77%) of clinicians performing skin examinations consisted of general practitioners, gynecologists, internists, surgeons, and urologists, with all physicians requiring a training course (40). The striking positive results of this study led to a nationwide screening program in Germany in 2008. Screenings were provided to all people over the age of 35. Unfortunately, mortality data from 2008 to 2013 returned to prescreening levels and mortality rates in Germany did not differ from neighboring countries (40).

Diagnostic Aids in Melanoma Screening

Various algorithms have been employed to help facilitate the identification of melanoma on physical examination. The ABCDE mnemonic, including asymmetry, border, color, diameter greater than 6 mm, and evolution, delineates worrisome features to look for when evaluating a lesion (Figure 1.2) (41). While the ABCDE criteria have been validated as a useful screening tool, physicians and individuals can miss early melanomas and amelanotic melanomas, which do not usually meet the criteria, and can overdiagnose benign lesions like seborrheic keratoses (41). The EFG criteria (elevated, firm, or growing lesion) can be useful for amelanotic or nodular melanomas. In addition, the “ugly duckling” sign is an important diagnostic pearl, and refers to overall pattern irregularity or a lesion that is distinct from other lesions on the patient’s body (42). In contrast, the “little red riding hood” sign describes a high-risk patient (fair skin with light-colored hair, a personal history of melanoma, or a large number of atypical-appearing nevi), in whom a melanoma may not stand out as completely different; therefore, a more diligent examination is required (42). The sign may also denote the finding of erythema or inflammation surrounding a cutaneous melanoma (42). Importantly, not all melanomas may present with these aforementioned clinical features; therefore, if a patient is worried about a particular skin lesion, it is important to address his or her suspicion and to lower the threshold to perform a skin biopsy.