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 carcinomas 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.
Exposure to ultraviolet radiation is the predominant risk factor for squamous cell and basal cell skin cancer, and is the only known environmental risk factor for melanoma. 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 76,250 new cases of melanoma were diagnosed in the United States in 2012, with approximately 9,180 deaths. Death from melanoma increased by 5.8% in the United States between 1990 and 2005 due to an increase in melanoma deaths in men, although there was a slight decrease in mortality from melanoma in women. The lifetime risk of melanoma for Caucasians is 1 in 39 for men and 1 in 58 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 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. High-risk groups, for whom screening efforts might make the largest impact, are older men and families with numerous cases of melanoma. Screening initiatives would be less likely to benefit the 10% of patients with melanomas that are nonpigmented or arise from the choroid of the eyes or mucosal surfaces.
In January 2012, the US Food and Drug Administration (FDA) announced the approval of the oral drug vismodegib (Erivedge) for the treatment of locally advanced and metastatic basal cell carcinoma. In the pivotal study, involving 96 patients, vismodegib (150 mg, once daily) shrank tumors or healed lesions in 43% of patients with locally advanced disease (27 of 63) and in 30% of patients with metastatic disease (10 of 33). The objective response rates for the two groups were 60% and 46%, respectively; progression-free survival for both groups was 9.5 months.
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 of 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 risk of recurrence in the setting of resected primary melanoma is higher, and expected survival in the setting of regionally advanced disease is significantly shorter.
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 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.
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.
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.
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 3% of 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, identification of the genes responsible for familial melanoma has greatly contributed to the understanding of the molecular pathophysiology of melanoma.
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 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 (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.
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.
With the incidence of melanoma still rising, it is clear that primary prevention efforts have not yet taken hold. The only approach firmly rooted in evidence is to minimize sun exposure. The use of sun-protective clothing appears to be the next best strategy. There are conflicting data regarding the protective effect of sunscreens for melanoma, although there is no controversy regarding their ability to prevent squamous cell and basal cell carcinomas. Protection against UV-A has been a long-standing feature of widely available suncreens, whereas UV-B protection has more recently been engineered into all mainstream products. It is possible that the more widespread of these wide-spectrum sunscreens will provide more meaningful protective effects over the coming decades.
There is incontrovertible evidence linking immunosuppression and squamous cell skin cancer. This increased risk applies to patients with acquired immunodeficiency syndrome (AIDS) as well as transplant recipients on chronic treatment with immunosuppressive medications. The risk of developing primary melanoma in the setting of immunosuppression is less well established, but there is some evidence that patients who have a history of melanoma are more likely to develop disease recurrence in the setting of immunosuppression.
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 with those with few benign nevi or without dysplastic nevi. However, it is critical to recognize that these preexisting moles, rather than precursor lesions, represent a risk factor for melanoma in most cases. 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. 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.
These 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.
History of Melanoma
Perhaps 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.
These lesions represent the precursor lesion for the vast majority of squamous cell skin cancers. They manifest as raised, nonpigmented lesions with a plaque-like surface. Typically, they have an erythematous base and arise on heavily sun-exposed skin. These lesions are typically treated with excision, cryotherapy, topical chemotherapy (5-fluorouracil [5-FU]), or immunotherapy (imiquimod). It is unclear what effect nonsurgical therapy has on the long-term risk of progression to squamous cell carcinoma, but the relatively indolent nature of most actinic keratoses suggests that nonsurgical therapy followed by close observation is reasonable, particularly for lesions arising on cosmetically sensitive areas such as the face.
Burns and Chronic Wounds
Burns (unrelated to sun exposure) and chronic wounds predispose to the formation of squamous cell carcinoma on permanently scarred areas (Margolin's ulcers). Although relatively uncommon, a tumor or ulcer occuring in a chronic wound should raise concern for malignancy and the area should be biopsied.