Skin cancer is the single most common form of cancer, accounting for more than 75% of all cancer diagnoses. More than 1 million cases of squamous cell and basal cell carcinoma are diagnosed annually, with a lifetime risk of more than one in five. The vast majority of skin cancers can be cured with surgery alone; resection is the mainstay of therapy, even for skin cancer involving regional lymph nodes or, in some cases, more distant metastatic sites.
Sun exposure is the predominant risk factor for squamous cell and basal cell skin cancers, and is the only known predisposing exposure for melanoma. It accounts for 90% of all skin cancer-related mortality. Melanoma accounts for 4% of all skin cancer diagnoses (60,000 new cases of invasive melanoma per year) but contributes to 75% of deaths from skin cancer. The natural history of melanoma that has spread to regional lymph nodes or beyond is minimally impacted by available systemic therapies.
Unlike many other cancers, the incidence of melanoma and death rates from melanoma continue to rise. The superficial nature of melanoma and other skin cancers supports campaigns to raise public awareness and healthcare provider expertise in detecting skin cancers at the earliest possible stage. Screening initiatives would be less likely to benefit the 10% of melanomas that are nonpigmented or arise from the choroid of the eyes or mucosal surfaces.
Epidemiology
Age The relationship between the incidence of melanoma and age is somewhat unique 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 highest incidence is among people between the ages of 45 and 54. 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. The incidence of squamous cell and basal cell carcinomas increases exponentially with age.
Gender Men are more likely than women to develop melanoma (60% higher incidence), and their prognosis is worse (130% higher risk of death from melanoma). The risk of recurrence in the setting of resected primary melanoma is higher, and their expected survival in the setting of regionally advanced disease is significantly shorter.
Location Basal cell cancers arise exclusively from cutaneous sites and are closely related to sites of skin that receive the most sun exposure, such as the scalp, face, neck, and arms. Squamous cell cancers can arise from numerous sites in the body, but the term squamous cell skin cancer is reserved for cutaneous sites. The vast majority of melanomas arise from cutaneous sites, but most cases of melanoma and most fatal cases arise from intermittently sun-exposed skin. A small percentage of melanomas arise on acral surfaces of the hands and feet, which tend to be diagnosed at a later stage. Melanoma can arise from melanocytes adjacent to the retina or within mucosal surfaces in the oropharynx, sinuses, rectum, or vulva. These lesions typically present with greater local invasion and risk of distant spread than cutaneous melanoma.
Geography The rates of melanoma and other skin cancers are highest 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 and melanoma.
Race Caucasians are by far the most susceptible race for melanomas, as well as squamous cell and basal cell 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. All racial groups are equally likely to develop melanoma on the acral surfaces of the hands and feet or mucosal surfaces. Therefore, melanomas arising from these sites represent nearly all cases of melanoma in these more darkly pigmented racial groups.
Survival 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 rate for melanomas that are less than 1 mm in thickness and that lack ulceration is 97%. Melanoma that is microscopically or macroscopically evident in regional nodes is associated with only a 30% likelihood of survival after 10 years. The presence of more distant metastatic disease is associated with only a 10% possibility of survival 10 years from initial recognition.
Etiology and risk factors
Genetic predisposition Although there are families in which melanoma can occur with high likelihood, an underlying genetic predisposition can only be found in 3% all cases. The pedigrees have been identified because of their high likelihood of a mutation carrier developing melanoma. Lower penetrance genotypes remain to be elucidated. Nonetheless, the identification of the genes responsible for familial melanoma has contributed greatly to the understanding of the molecular pathophysiology of melanoma.
The clinical observations that patients with multiple dysplastic nevi were at greater risk of developing 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 to harbor germline mutations in roughly 50% of melanoma pedigrees: CDKN2A and CDK4. CDKN2A enocodes 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 is a rare inherited disorder in which DNA repair mechanisms are compromised, particularly in response to ultraviolet (UV) light. Mutations in XP genes A though G have been identified as the underlying molecular event. Squamous cell and basal cell carcinomas and melanoma are prevalent in this population and 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 melanocortin-1 receptor (MC1R) has been clearly implicated in pigmentation of skin and hair and, more recently, to melanoma predisposition. It has been known for decades that melanoma is more prevalent among fair-skinned individuals with red or blond hair. Furthermore, blond-haired individuals with an inability to tan are at substantially greater risk of developing melanoma than blond-haired individuals 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.
Exposure 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 sun burns, 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 recently 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 than those who are sun exposed. 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.
