Damian Sendler: Cancer diagnoses for melanoma make up 1.7 percent worldwide, the fifth most common cancer among American adults. Over the past 40 years, the incidence of melanoma in the United States has risen by more than 320 percent. Since 2011, ten new targeted or immunotherapy agents have been approved, which has resulted in a 30% reduction in mortality in the United States. As a result of UV radiation, half of patients have BRAF mutations that can be targeted with oral BRAF/MEK inhibitor combinations, while checkpoint inhibitors are used to reactivate the immune system. Stage IV disease survival remains at 29.8% despite an increase in the overall 5-year survival rate to 93.3% in the United States. The average age of diagnosis for melanoma is 65 for white, older men. Although indoor tanning beds, immunosuppression, family history, and rare congenital diseases, moles, and obesity all contribute to the disease, outdoor UV exposure without protection is the primary risk factor. Sunscreen use has increased and the incidence of melanoma has decreased since primary prevention programs were implemented in Australia in 1988, when the country’s melanoma rate was at its highest. Melanoma incidence in the United States is expected to peak between 2022 and 2026. In the US, less than 40 percent of people say they use broad-spectrum sunscreen with an SPF greater than 30 every day to protect themselves from the sun’s harmful ultraviolet rays (UVA/UVB rays). A return on investment of 2-4 times is predicted for a US sun protection education program. Melanoma mortality has been reduced by lesion-directed skin screening programs, particularly in high-risk individuals.
Damian Jacob Sendler: Melanoma is a cancer of the melanocytes, the pigment-producing cells in the epidermis’ basal layer that produce melanin (pigment). The neural crest origins of melanocytes mean that they produce an abundance of signaling molecules and factors that facilitate migration and metastasis in malignant cells. Melanoma accounts for more than 80% of all skin cancer deaths, despite making up only 1% of all skin cancers.
Dr. Sendler: There are numerous clinical subtypes of melanoma, each with a unique manifestation, demographics, and molecular profile. SSM is the most common form of melanoma among fair-skinned individuals and has a good prognosis due to a low Breslow thickness, which also depends on the earlier time of diagnosis. A type of melanoma that can develop on the rough, bare skin of the hands, feet, and nails called acral lentiginous melanoma is more common in people of color. Mucosal or uveal melanoma is rare, but it can occur without sun exposure [2]. Over half of patients with stage IV uveal melanoma have a poor prognosis, according to a recent study.
Over the last few decades, the incidence of melanoma has risen in developed countries with a preponderance of fair skin [4]. One in five cancer diagnoses in the United States is now melanoma. According to GLOBOCAN, we analyzed incidence, mortality and survival using 2020 global data. In addition, we discuss the most recent international efforts to prevent melanoma [5]. The most common risk factors, the effectiveness of preventative measures, and epidemiological trends are discussed below.
In the US, melanoma is the fifth most common cancer diagnosis, accounting for 5.6 percent of all cancer diagnoses in 2021, according to the most recent SEER data. White males are more likely than white females to develop melanoma, with incidence rates (per 100,000 people) of 34.7 and 22.1, respectively, among white men and women. Blacks had a male and female incidence of 1.0 and 0.9, respectively, while Hispanics had a male and female incidence of 5.0. It is estimated that 65.7 percent of diagnoses are made between the ages of 55 and 84 [1].
The incidence of melanoma has grown at the fastest rate among cancers in developed countries (Figure 2). From 7.9/100,000 in 1975 to 25.3/100,000 in 2018, the melanoma incidence in the United States increased by over 320 percent. Since 2007, the Journal of Investigative Dermatology has published a model predicting an increase in incidence from 31.0 to 43.7 among white American adults by 2027. Between 1982 and 2011, the incidence in the UK rose from 5.8 to 19.8 while it rose from 13.0 to 28.3 in Sweden and from 26.4 to 51.6 in Australia. In Australia, incidence peaked in 2005 and is expected to continue to decline as a result of effective public health campaigns and increased access to sunscreens. The incidence of melanoma in the United States is expected to peak around 2022–2026, while incidence in Sweden and northern Europe is unlikely to stabilize before 2030 [6].
Melanoma’s 5-year survival rate has increased from 81.9 percent in 1975 to 93.3 percent in 2011–2017, according to SEER data. Stage I–II patients have a 5-year survival rate of 99.4 percent, while stage III patients have a survival rate of 68.0 percent and stage IV patients have a survival rate of 29.8 percent. Most diagnoses are made in stages I-II (Figure 4), with only four percent of diagnoses being stage IV (Figure 4).
UV exposure is the most important risk factor for skin melanoma, but genetics, melanin, and the wavelength of the UV light all play a role.
Unrepaired nucleotide excision repair (NER) can cause errors in DNA replication, which in turn can lead to mutations in cell signaling molecules and, ultimately, cancer [8]. UV light is known to induce DNA photoproducts, most commonly thymidine-dimers. These patients are at a much greater risk of developing skin cancer, as well as neurodegenerative diseases like Alzheimer’s and Parkinson’s disease [9,10].
In terms of genotoxicity, UVB light (wavelength: 280–320 nm) is 1000 times more potent per photon than UVA light (wavelength: 320–400 nm), despite the fact that UVA environmental exposure can be up to 20–40 times greater depending on the time of year, season, latitude, and altitude [11,12]. Most non-broad-spectrum sunscreens do not filter out UVA in addition to UVB, which increases UVA exposure through windows and sunbeds. It has been discovered that unlike the UVB-induced pyrimidine dimers, UVA-induced oxidative (aerobic) damage to DNA is repaired via a different system (base excision repair) than the UV-induced pyrimidine dimers [13,14,15]. It appears that UVA appears to have a lower rate of DNA repair, which results in a higher rate of mutations per photoproduct in melanocytes.
Damian Sendler
The molecular profile of cancer varies greatly depending on the type of melanoma, the prognosis, and the treatment response to UV-induced mutations. NRAS and BRAF, two members of the mitogen-activated protein kinase (MAP-K) family, are among the most frequently mutated proteins. Small molecular inhibitors of BRAF + MEK are now the first-line treatment for patients with superficial-spreading melanoma (SSM) who have BRAF mutations, which are more common in younger patients with more nevi and sun exposure [16,17,18]. A total of 0% of SSM cases have KIT mutations, while up to 20% of acral lentiginous (ALM) and mucosal (MM) cases have KIT mutations [19]. There is a link between uveal melanoma and mutations in the genes GNAQ and GNA-11, not with sun damage or MAP-K mutations [20]. Stage IV cancer patients are more likely to have UV-induced mutations in the tumor suppressor p53, which are linked to a worse prognosis [15]. UV-induced mutations can also affect NER, increasing the risk of cancer [8].
Phaeomelanin, which is found in greater abundance in those with fair skin and red hair, is less effective at protecting against UV radiation than eumelanin. Eumelanin, which scatters UV rays to protect DNA, also reduces cutaneous vitamin D3 production, which is why humans who left Africa for higher latitudes (where UV exposure is less) were selected for lighter skin [11,21,22].
Damien Sendler: The International Agency for Research on Cancer (IACR) has identified tanning bed radiation as a carcinogen due to higher levels of UVA and UVB exposure than that of daily sun exposure (for most latitudes) [23], yet an estimated 7.8 million women and 1.9 million men use tanning beds each year. The amount of time spent in a tanning bed, the number of sessions, or the number of years of tanning bed use has been linked to an increased risk of melanoma [24]. White, non-Hispanic young women continue to have the highest rates of indoor tanning among high school students in the United States [25]. [7.4 percent in 2009 to 7.3 percent in 2015]. According to a JAMA Dermatology economic analysis from 2020, the ban on indoor tanning among those under 35 could prevent 448,000 cases of melanomas. [26].
Langerhans and dendritic cells’ immunosurveillance is impaired, as is T-cell and NK-cell activation in response to aberrant melanoma cells when exposed to low UVA and UVB doses. Melanoma is more common in people who have been immunosuppressed in some way, whether iatrogenic or as a result of HIV [27,28,29,30]. Immunotherapy using monoclonal antibodies that stimulate T cells to recognize and destroy cancer cells may be more effective against melanoma because of these findings. Ipilimumab (Yervoy) is a CTLA-4 inhibitor that first received FDA approval in 2011 for treating melanoma. It has since been approved for use in combination with other drugs to treat a wide range of cancers. For patients with stage III and IV disease, PD-1 and PDL-1 inhibition drugs like Pembro and Nivolumab (tradenames: Opdivo, Keytruda) have since been approved in various combinations. An FDA-approved combination of atezolizumab (Tecentriq), vemurafenib (Zelboraf), and cobimetinib (Cotellic) for the treatment of unresectable or metastatic BRAF V600 positive melanoma was approved in 2020 [31]. Uveal melanoma patients with a poor prognosis have benefited from immunotherapies in small clinical trials [32]. [33, 34].
Damian Jacob Sendler
Melanoma precursors and risk indicators include melanocyte growths known as moles or nevi. Those under the age of 40 had a 0.0005 percent annual incidence rate of melanoma, while those over the age of 60 were found to have a 0.003 percent annual incidence rate. According to one study, those with at least 100 moles have a seven-fold increased risk of developing malignant melanoma. According to the researchers, moles that persist into old age are more likely to develop cancer. According to recommendations, these moles should be monitored based on the ABCDE criteria (asymmetry, border irregularity, color variation, diameter greater than 6 mm, and evolution) and resected with margins of at least 2 millimeters if suspected [35].
There are only a handful of congenital syndromes, such as congenital nevi and mutations, that have been identified in 10% of melanoma patients. As many as 30% of hereditary melanomas may be caused by mutations in the CDKN2A gene, which is extremely rare in sporadic cases.
Damian Jacob Markiewicz Sendler: Dermatological malignant tumors of the skin and gallbladder have been linked to dysplastic nevus syndrome (DNS), an extremely rare congenital disease that affects atypical nevi. Neurofibromatosis type 1 and other endocrine disorders are linked to DNS [40]. Pregnancy-related melanoma has also been linked to the use of DNS [41]. Other cancers aren’t affected by DNS, either. Those who are predisposed to DNS or other types of familial melanoma should have their moles and skin checked regularly, and they should also avoid high-risk activities like prolonged sun exposure without protection [39]. Children with CMN (congenital melanocytic nevi) have an increased risk of developing neurocutaneous melanocytosis and melanoma because they are born with or develop many large moles. NRAS mutations are the most frequently implicated. Prophylactic MEK inhibitors for CMN patients are being tested in clinical trials as part of an interdisciplinary approach to mole removal and monitoring [42].
Obesity has been linked to an increased risk of melanoma in some studies, but this is not universal. Obese patients who receive targeted treatments and immunotherapies have shown improved survival rates in recent studies. Because obesity appears to activate BRAF V600E oncogene activity and suppress immunosurveillance through metabolic signaling and BRAF inhibitor therapies and immunotherapies that specifically target these pathways, it may explain why obese patients have an above-average PFS and OS on these therapies [43,44].
It is imperative that the United States take a cue from developed countries like Australia, where public health initiatives have been successful in slowing the rise in melanoma cases.
The American Cancer Society (ACS) estimates that the use of tobacco, obesity, poor diet, alcohol, and certain viruses cause 45 percent of all cancer deaths. Skin cancer rates are significantly reduced decades later if people regularly apply sunblock, according to numerous studies [46]. While the American Cancer Society (ACS) recommends avoiding direct sunlight from midday until four o’clock, it also recommends wearing protective clothing and using broad-spectrum sunscreen with an SPF of 30 or higher [47]. The American Cancer Society (ACS) also advises against using tanning beds or other artificial sources of UV exposure. However, in a 2018 online survey of more than 3000 Americans, only 38.8 percent admitted to using sunscreen on their face, neck, and chest, while only 19.9 percent admitted to applying sunscreen to their entire exposed body [23].
Victoria, Australia, has had the SunSmart program running since 1988, using television commercials to promote the use of sun protection such as hats and sunscreen. Sunburn incidence had decreased by half by 2002, according to a meta-analysis of nine cross-sectional studies, and people exposed to the advertising encouraged more frequent use of sun protection [48]. The SunSmart school accreditation program mandated that grade-school students wear hats, seek out shade, and engage in sun-protective behavior as role models. Over the past two decades, there has been a dramatic increase in the percentage of schools in Victoria that have implemented sun protection policies.
The US has had some success with prevention initiatives, despite the fact that they are more limited in scope. More than 11,000 cases of skin cancer and 50 deaths were averted as a result of the SunWise program in 2008, according to an estimate. These results indicate that more money should be invested in sun-protection measures [50].
Clinical skin cancer screening for asymptomatic adults without a history of malignancy or skin lesions was rejected by the US Preventive Services Task Force in 2016 because of a lack of evidence. The recommendation is to screen adults who have a family history, a genetic predisposition to skin cancer, a history of sun exposure, or fair skin. A 2017 meta-analysis of 15 studies found a clinical benefit to skin cancer screening programs. Belgian researchers found that lesion-directed skin exams had similar detection rates to whole-body skin exams that take six times longer [53]. Skin self-examination evidence was highly variable, and performance was strongly linked to the presence of a wall mirror [54].
The incidence of melanoma is expected to rise steadily in the coming decades, making it one of the most common cancer diagnoses in the developed world. Tissue-targeted and immune-based therapies have reduced mortality, but patients diagnosed with stage IV disease still have a dismal survival rate. In order to keep healthcare costs down and reduce morbidity and mortality, preventative measures are essential. Melanoma incidence in Australia has been reduced significantly by educational programs that target risk factors such as UV exposure without broad-spectrum sunscreen, indoor tanning, immunosuppression, and obesity. Risk factors include family history, predisposing lifestyles/occupations, and high-risk populations such as older, white men. Screening is recommended for those with risk factors.
