Melanoma: Epidemiology, Diagnosis, and Treatment

"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Melanoma is the rarest of all skin cancers but paradoxically the deadliest, accounting for about 1% of all new cases of skin cancer in the U.S. but more than 80% of the deaths.

About 100,000 new melanoma diagnoses will occur in the U.S. during 2022, with a predominance in men (57,000 vs 42,000 for women). An estimated 7,650 people will die of melanoma this year: 5,080 men and 2,570 women.

Globally the incidence of melanoma has increased substantially for decades, primarily in countries and geographic regions inhabited predominantly by light-skinned people. In the U.S., for example, melanoma incidence increased by 320% from 1975 to about 2000. Similar large increases in case volume occurred in England, Sweden, and Australia.

More recently, melanoma incidence in the U.S. has decreased, particularly among people younger than 50. From 2005 to 2018, melanoma incidence declined about 1% annually in adults younger than 50, and from 2014 to 2018 incidence stabilized among older adults.

Melanoma mortality in the U.S. has declined by 30% since 2011, coinciding with the approval of multiple new targeted therapies and immunotherapies.

Melanoma occurs most often in older white men. The mean age at diagnosis is 65, and two thirds of all new cases involve people ages 55 to 84. Melanoma incidence is 34.7 per 100,000 among white men and 22.1 per 100,000 in white women -- compared with incidence rates of 1.0 and 0.9 per 100,000 among Black men and women and 5.0 per 100,000 in Hispanic men and women.

Melanoma Origin and Risk Factors

Melanoma arises in melanocytes, the melanin (pigment)-producing cells, located in the basal layer of the epidermis. Melanocytes express numerous signaling molecules and biological factors that promote proliferation, migration, and metastasis following malignant transformation. Melanocytes continue to express melanin after transformation, and many melanomas are dark brown or black. Some, however, are light brown, pink, or even white.

The odds of developing melanoma involve a combination of modifiable and nonmodifiable risk factors. As with more common types of skin cancer, the primary risk factor for melanoma is exposure to ultraviolet (UV) light, which induces photomodified DNA products. If not corrected by nucleotide excision repair, the modified DNA products can cause errors in DNA replication, mutations in cell-signaling molecules, and carcinogenesis.

Both UVA and UVB can exert genotoxic effects on the skin. UVB is the more potent (on a per-photon basis) of the two forms of UV light, but environmental exposure to UVA is greater, depending on the time of day, season, latitude, and altitude. UVA exposure is greater through windows and in tanning beds, and most broad-spectrum sunscreens do not filter UVA as well as UVB.

Additionally, UVA can cause oxidative damage to DNA, which has a different type of repair mechanism and seems more resistant to DNA repair.

Inherent physical traits also influence the risk of melanoma. The combination of fair skin, red or blond hair, blue eyes, and freckles significantly increases the risk of developing melanoma and other skin cancers. People who tend to sunburn rather than tan also are at greater risk.

The presence of numerous or atypical moles, including dysplastic nevi, increases the risk of melanoma. A family history of melanoma increases the likelihood, and about 10% of melanomas involve people with a positive family history.

Beyond family history, mutations in certain inherited genes can cause melanoma, but such cases are rare. Recent studies also have shown interpersonal variation in how molecular components of the skin respond to UV damage.

Circumstances surrounding exposure to UV light figure into the risk equation for melanoma. Two types of UV exposure, both potentially modifiable, appear to figure prominently in a person's risk. Many people with melanoma have an early history of sunburn or intense sun exposures. Some researchers hypothesize that the early exposure induces DNA damage in melanocytes and sets in motion a chain of molecular reactions that lead to melanoma years later.

A second type of circumstance relates to chronic sun exposure, which may lead to melanomas that occur on skin areas that are chronically exposed to the sun, such as the arms, neck, and face. Use of artificial tanning devices or tanning booths have a significant association with melanoma risk and may contribute to either type of circumstantial exposure.

Immunosuppressed individuals also have an increased risk of melanoma. The observation is consistent with evidence that low doses of UVA or UVB are associated with decreased immunosurveillance by multiple types of immune cells.

Melanoma Symptoms and Recognition

Melanomas can occur anywhere on any skin area, including areas that have little sun exposure, such as the soles of the feet and inside the mouth. Though more common in white men, melanoma occurs in both sexes and in people of all skin colors.

The most common sites of melanoma are the upper back, torso, lower legs, head, and neck, although location can vary by a person's age, sex, and race. People with skin of color are more likely to develop melanomas in areas with little or no sun exposure: the palms of the hands, soles of the feet, groin, under the nails, and inside the mouth.

Melanomas often arise from atypical moles, which are generally larger and not uniform in color. They may have irregular borders and occur in large numbers, as compared with regular moles. Any new mole, but especially one that appears atypical or irregular in shape or appearance, warrants suspicion. The presence of numerous moles (more than 50 and especially more than 100) is a risk factor for melanoma. A large mole or one that develops a rough or otherwise irregular surface could harbor a melanoma.

Beyond moles, any change in the appearance of a skin area or existing mole or other skin growth could represent an early sign of developing melanoma. Continual itching, oozing, or bleeding from a mole or other skin growth should be considered suspicious, although most melanomas are not painful.

Diagnosis of Melanoma

Biopsy of a suspicious mole or other skin lesion remains the most common approach to diagnosis and is the only means to a definitive diagnosis. Several emerging technologies have shown promise for noninvasive diagnosis but are not yet widely used or available in the U.S.

Reflectance confocal microscopy (RCM) permits visualization below the skin surface without an incision or tissue removal. Widely used in Europe, RCM is available at select centers in the U.S. and is particularly useful for evaluating patients who have multiple unusual moles or otherwise suspicious lesions, reducing the number of biopsies.

Adhesive patch testing continues to be evaluated for diagnostic utility. Applied to a skin area or lesion of interest, the patch peels off a layer of skin cells when removed, and the cells can be evaluated for specific genetic changes associated with melanoma. If any changes are present, a biopsy is indicated; if no changes are found, the lesion can be observed.

Melanoma Treatment Approaches

Although the approach to treatment obviously depends on the disease stage at diagnosis, few areas of oncology have undergone more therapeutic transformations than melanoma. Effective treatments have evolved for various stages of the disease, including metastatic melanoma, which have dramatically changed the prognosis for patients at time of diagnosis.

Surgery remains the cornerstone of treatment for early-stage melanoma. Most stages 0-II melanomas can be cured with surgery alone. Moreover, the DecisionDx-Melanoma laboratory test can be used to analyze gene-expression patterns in biopsy specimens to help determine the metastatic potential of stages I-II lesions. The test can inform decisions about the need for sentinel lymph node biopsy or additional treatment.

Surgery for the primary tumor remains essential to the treatment of stage III (locally advanced) melanoma. However, effective adjuvant therapy has evolved with advances in targeted agents and immunotherapy, which has improved outcomes with better tolerability. Neoadjuvant therapy may be recommended in some cases in an effort to improve surgical outcomes. Recently, adjuvant immune therapy for high-risk stage II patients has also been FDA approved.

Therapeutic development has produced multiple new options for unresectable and metastatic melanoma. Targeted therapies and immunotherapy substantially prolong survival in advanced melanoma as compared with chemotherapy.

Biomarker testing continues to evolve but offers the potential to match patients with the most appropriate therapy for the molecular characteristics of the tumors. BRAF testing is standard of care to identify patients that would benefit from combination BRAF/MEK-targeted therapies. Molecular profiling of metastatic tumors also offers clinical trial matching for patients with other identified molecular drivers.

Melanoma: Long-Term Survival

Survival for melanoma has increased steadily in recent decades, particularly among patients with more advanced disease stages. More than 80% of melanomas are diagnosed at stages I-II and fewer than 5% at stage IV (metastatic). Across all stages, the 5-year survival rate for melanoma is 93%, ranging from 99% for localized (stages I-II) to 68% for locally advanced to 30% for stage IV (metastatic). Recent data have demonstrated the significant advances with immune therapy leading to 49% overall survival rates at 6.5 years for patients treated on a clinical trial with combination immune checkpoint inhibitors.

The survival statistics still emphasize the importance of early diagnosis and treatment. Public awareness plays a major role in achieving the goal of early diagnosis and treatment. Australia historically has had among the world's highest melanoma incidence and mortality, but rates peaked in 2005 and have declined steadily since then, coinciding with a strong public health campaign to raise awareness of the disease.