Skin cancer is the most common form of malignancy, accounting for more than 75% of all cancer diagnoses. More than 3 million cases of squamous cell carcinomas, basal cell carcinomas, and melanomas are diagnosed annually in the US, with one in five Americans developing skin cancer. The vast majority of skin cancers can be cured via localized therapies including topical therapy, radiation therapy, and simple surgical interventions. Resection with wide surgical margins remains the mainstay of therapy for melanoma.
The interaction of genes and the environment is responsible for most skin cancers. Exposure to ultraviolet radiation is the best-known and best-studied environmental risk factor for squamous cell and basal cell skin cancer, and is the only known environmental risk factor for melanoma. Genetic predisposition to skin cancer, which may be expressed by phenotypic traits such as red hair or the presence of many nevi, also plays a significant role. Genetic susceptibility to melanoma clearly varies across the population and correlates to a large degree with light skin, hair, and eye color. Melanoma contributes to 75% of deaths from skin cancer. An estimated 73,870 new cases of melanoma of the skin will be diagnosed in the United States in 2015, with approximately 9,940 deaths. The overall death rate from melanoma increased by 5.8% in the United States between 1990 and 2005; this increase was the result of a significant rise in melanoma deaths in men. The mortality rate in women over the same period of time actually showed a slight decrease. The lifetime risk of melanoma for Caucasians is 1 in 35 for men and 1 in 54 for women in the United States. The 5-year survival was 92% of patients diagnosed with melanoma in the United States between 1996 and 2004, an increase of 10% compared with the years 1975 through 1977. This is almost certainly due to an increase in early detection.
The knowledge that melanoma and other skin cancers begin their growth within the superficial layers of the skin supports campaigns to raise public awareness and healthcare provider expertise in detecting skin cancers at the earliest possible stage. High-risk groups, for whom screening efforts might make the largest impact, are older men, individuals with many nevi, those with a personal or family history of skin cancer, and families with numerous cases of melanoma, just to mention a few of the high-risk groups.
The vast majority of melanomas arise from cutaneous sites. Most arise from intermittently sun-exposed skin. A small percentage arise on acral surfaces of the hands and feet. Melanoma can arise from melanocytes adjacent to the retina or within mucosal surfaces in the oropharynx, sinuses, rectum, or vulva. These noncutaneous melanomas have distinct clinical and biological features when compared to cutaneous melanoma.
The relationship between the incidence of melanoma and age is unusual in comparison to other common cancers. There is not an exponential increase in risk with age but rather a more even distribution across age groups. The median age at diagnosis of melanoma is 53 years, almost 10 years younger than the median age of diagnosis of most common cancers. Forty-two percent of cases present in people younger than age 55, contributing to the third highest number of years of life lost across all cancers. In contrast, the incidence of squamous cell and basal cell carcinomas increases exponentially with age.
Men are more likely than women to develop melanoma (67% higher incidence), and their prognosis is worse (136% higher risk of death from melanoma). The reasons for this are unclear.
Caucasians are by far the most susceptible race for all skin cancers. Hispanics have a lower incidence but represent the group at next-highest risk. Asians and African Americans have the lowest rates of skin cancer. For those populations, cutaneous melanomas arising from sun-exposed sites are uncommon but not unseen. The most common type of primary melanoma in low-risk groups is the acral subtype, occurring on the hands and feet.
The rates of melanoma and other skin cancers are highest in countries where fair-skinned Caucasians migrated to lower latitudes, with annual sun exposure that is substantially higher than their historically native climates. Australia, New Zealand, South Africa, and Israel bear a disproportionate burden of skin cancer. In Australia, melanoma is the third most common cancer. In the United States, Hawaii and the desert Southwest have the highest rates of skin cancer of all kinds, including melanoma.
Skin cancers that are confined to the skin at presentation and with adequate staging evaluation have a high rate of cure. The 10-year survival of patients with invasive melanomas that are 1 mm or less in thickness and that lack ulceration is 97%. Melanoma that is microscopically present in regional lymph nodes is associated with a 10-year survival of 50% to 60%; when macroscopic or clinically apparent lymph nodes are detected, the 10-year survival is only 30% to 40%. The presence of more distant metastatic disease is associated with only a 5% possibility of survival 10 years from initial recognition.
Although there are families in which melanoma can occur with high likelihood, an underlying genetic predisposition can only be found in only a small percentage of patients. These pedigrees have been identified because of their high likelihood of a mutation carrier developing melanoma. Lower-penetrance genotypes remain to be elucidated. Nonetheless, identification of the genes responsible for familial melanoma has greatly contributed to the understanding of the molecular pathophysiology of the disease.
The clinical observation that patients with multiple dysplastic nevi were at greater risk for melanoma and that many such patients came from families with multiple affected individuals provided the first insight into a melanoma progression model that might be accelerated based on inborn genetic abnormalities. Two highly related genes were discovered in roughly 50% of melanoma pedigrees: CDKN2A and CDK4. CDKN2A encodes two products via alternate splicing of messenger RNA: p16INK4A and p14ARF. Each of these tumor suppressor genes exerts an inhibitory effect on cell cycle progression.
Xeroderma pigmentosum (XP) is a rare inherited disorder in which DNA repair following UV damage is impaired. Mutations in XP genes A through G have been identified as the underlying molecular event. Squamous cell and basal cell carcinomas and melanoma are prevalent in this population at a young age. The near-complete penetrance of melanoma in these patients emphasizes the critical balance between UV-induced DNA damage and repair in risk for skin cancer. As DNA damage repair is mediated by a complex network of sensor and effector proteins, variability in the function of this system almost certainly underlies the variability in risk among the fair-skinned population.
Genetic variability in the melanocortin-1 receptor (MC1R) has been clearly implicated in pigmentation of skin and hair and, more recently, in melanoma predisposition. It has been known for decades that melanoma is more prevalent among fair-skinned individuals with red or blond hair. Furthermore, blondes with an inability to tan are at substantially greater risk of developing melanoma than those who tan readily. Polymorphisms, distinct from mutations, in MC1R appear to account for skin and hair color differences among Caucasians. It appears that individuals with melanocortin receptors that have a muted response to increased melanocortin expression following sun exposure suffer the greatest UV-induced genetic damage, leading to a greater risk of melanoma.
History of melanoma
The single greatest clinical risk factor for melanoma is a personal history of melanoma. In addition to having surveillance for local and distant recurrence related to their prior melanoma, these individuals require lifelong observation for the emergence of a new primary melanoma; their risk is 10 times greater than that of the general Caucasian population.
Even the inheritance of CDKN2A and CDK4 mutations is insufficient to lead to melanoma in all carriers. It is clear that multiple genetic changes are required to give rise to invasive disease. UV damage is the best-described modifiable risk factor for melanoma, as well as squamous cell and basal cell skin cancers. It is believed that the acquired or somatic genetic changes that give rise to melanoma occur as a consequence of UV-induced genetic damage.
Epidemiologic data relate the risk of melanoma most closely to a connection between cumulative sun exposure, severe sunburns, or sun exposure during childhood, depending on the study. The disagreement between studies likely stems from methodologic differences in obtaining a sun exposure history, a heterogeneous effect of sun exposure and risk depending on the underlying genetic composition of the study population, or both. It has been clarified that melanoma arising on intermittently sun-exposed skin (such as the trunk) has its peak incidence among younger individuals and declines severely with increasing age. On the other hand, melanoma arising from chronically sun-damaged skin (such as the face, neck, and upper extremities) has the highest incidence in older individuals. With the rise in popularity of indoor tanning salons, data indicate that those who use them are at higher risk of melanoma. This may account for the recent rise in melanoma incidence observed in young women in the United States. There is little dispute regarding the causal link between sun exposure or tanning salon use and risk of melanoma; however, there is disagreement regarding the constituents of light (UV-A or UV-B) that contribute most to genetic damage. Laboratory studies support a connection for both and suggest that prevention strategies must take the entire UV light spectrum into account.
Patients with numerous benign nevi (small, regularly shaped, and uniformly pigmented moles) are at increased risk of melanoma, as are patients with relatively few dysplastic nevi (large, irregularly shaped, and heterogeneously pigmented moles). Patients in either group may have a fivefold increased risk of developing melanoma compared to those with few benign nevi or without dysplastic nevi.
Atypical, or dysplastic, nevi represent a risk factor for melanoma in that individual lesions can occasionally progress to invasive melanoma. More commonly, the presence of dysplastic nevi suggests an individual at risk for melanoma formation at other sites. The clinical definition of atypical nevi has never been formally established but generally refers to the presence of one or two of the ABCD features (see Signs and Symptoms section). Cutaneous photography has been routinely incorporated in the follow-up of patients with multiple clinically dysplastic nevi in specialized pigmented lesion clinics. Full-body cutaneous photography is increasingly available to patients and provides an objective baseline from which to judge change of pre-existing lesions or the appearance of new lesions. The vast majority of dysplastic nevi do not give rise to melanoma. There seems to be little value in resecting every nevus that appears dysplastic on clinical grounds and does not adequately address the risk that patients face of developing melanoma in sites where no precursor lesion is found. Surveying the skin regularly for new or changing moles has been the most widely adopted strategy for educating patients and healthcare providers. In patients older than 25 to 30 years, new mole formation warrants examination by a provider who is comfortable making the diagnosis of melanoma.
Congenital nevi are relatively rare compared with acquired nevi. In general, they do not suggest a predisposition to melanoma. A small number of children are born with so-called giant congenital nevi, also referred to as bathing trunk nevi. Melanoma arising from within a giant congenital nevus is a well-described phenomenon and is one reason that staged resection of such lesions is recommended for many children and adolescents.
Although there is incontrovertible evidence linking immunosuppression and squamous cell skin cancer, the risk of developing primary melanoma in the setting of immunosuppression is less well established. There is some evidence that patients who have a history of melanoma are more likely to develop disease recurrence in the setting of immunosuppression.