Melanoma

Multiple factors contribute to melanoma risk. Researchers are still learning how sun exposure, complexion, age, genetic makeup, and family history all interact to contribute to an individual's melanoma risk.

Sun exposure

Exposure to ultraviolet (UV) rays, particularly UVB rays, is the major environmental risk factor for melanoma. Sun exposure causes more than 90% of all melanomas in the U.S. A history of blistering sunburns, especially as a child, can increase risk. Airline pilots and cabin crews who are routinely exposed to higher levels of UV rays that occur at high altitudes have melanoma at twice the rate of the general population. 

To avoid sun exposure, wear a wide-brimmed hat, clothes that cover your skin, and sunglasses. If you cannot cover yourself or otherwise avoid the sun, use and reapply sunscreen with at least sun protection factor (SPF) 15, even on cloudy days. Sunbathing and indoor tanning increase melanoma risk and should be avoided.

Even intermittent sun exposure, like that of an office worker who spends weekends outside, can significantly increase the risk of developing melanoma. Researchers do not fully understand how much sun exposure is necessary to trigger melanoma, so it is best to avoid it as much as possible.

Skin type

Anyone can develop melanoma. However, people with fair complexions are at much greater risk than the rest of the population. For example, someone with blue eyes and extremely fair skin that always burns will be at greater risk than someone with olive-colored skin that rarely burns.

African Americans are about 1/20th as likely as Caucasians to develop melanoma. Hispanic individuals are 1/6th as likely to develop it. However, mortality rates for melanoma are higher in darker-skinned people, who tend to have more advanced melanoma once it is detected. Individuals with more pigmentation are more likely to develop melanoma on the palms of their hands, soles of their feet, and under their fingernails. These regions account for more than half of melanomas in African Americans but fewer than 1 out of 10 of melanomas in Caucasians.

Having large numbers of atypical moles is also an important risk factor for melanoma.

Age

Older men are at the highest risk for melanoma, according to the National Cancer Institute. However, melanoma is among the most common cancers in adolescents 15 to 19 years old and young adults 20 to 24 years old. It is the second most common cancer in people 25-29 years old.

Family history

While most melanomas are caused by random mutations that happen after birth, you can also inherit genes that make you more susceptible to melanoma. Risk increases if someone has a first-degree relative (i.e., parent, sibling or child) who has had multiple melanomas, or two or more first-degree relatives who have had even a single melanoma. About 10% of people with melanoma have had a relative with melanoma.

Researchers have discovered some of the genes associated with hereditary melanoma. About half of people who develop familial melanoma have mutations of at least one of the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP or TERT. The exact manner in which melanoma develops due to these mutations is not well understood and researchers still do not understand the genetic mechanisms behind hereditary melanoma in people with no known mutations.

Until researchers understand more about the genes underlying melanoma risk, screening the general population for these genes is not recommended. However, genetic testing may be appropriate for people with certain risk factors.

If you have the following risk factors, the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommend that you talk to a genetic counselor about testing:

• A personal history of three or more primary melanomas
• A personal history of melanoma and pancreatic cancer
• A personal history of melanoma and astrocytoma (brain tumor)
• Three or more cases of melanoma and/or pancreatic cancer in first-degree relatives, such as a parent or sibling
• Melanoma and astrocytoma in two first-degree relatives

Other risk factors

• Exposure to certain chemicals and other environmental risk factors like: arsenic in drinking water, radiation, solvents, vinyl chloride, heavy metals, and polychlorinated biphenyls (PCBs)
• Conditions that weaken the immune system

Most moles or dark spots on the skin are harmless. But new spots or changes in the size or appearance of existing moles or spots are the most important warning sign of melanoma. 

Melanoma in men often appears between the shoulders and hips. In women, it is more often found on the arms or legs.

Typical early warning signs of melanoma can be remembered using the ABCDE criteria for a changing mole:

• Asymmetry: The two halves of the mole do not match.
• Border irregularity: The edges of the mole or pigmented area are blurry, ragged, or notched.
• Color: The color is not uniform and may be shades of brown or black, or include pink, red, white, or blue.
• Diameter: A mole or pigmentation with a diameter greater than a quarter of an inch (6 mm) may be a melanoma. Also, any mole that grows in diameter should be checked by a healthcare practitioner.
• Evolving: Melanomas may change appearance over time. This is something to watch for in dome-shaped and non-pigmented melanomas that may not have the ABCD characteristics.

Not every melanoma will have ABCDE characteristics. Another warning sign of melanoma is an "ugly duckling" lesion. These lesions may simply look different from the rest on a person's body, indicating a potential melanoma.

Other signs and symptoms of melanoma include a mole or pigmentation that is:

• Itching
• Bleeding or oozing
• Ulcerated, or an open sore
• Painful
• Black and blue
• Scaly

Symptoms like itching, bleeding, pain and ulceration may not appear until the melanoma has grown deeper into the skin.

Since early detection is key to a good prognosis for melanoma, it is important that you and your healthcare provider are aware of any changing spots on your skin. If you have a spot that seems unusual, let your provider know.

Early detection and treatment are key to curing melanoma. Melanoma screening includes regular, full-body skin exams performed by a healthcare practitioner and self-exams performed at home.

Medical organizations conflict on whether to recommend melanoma screening. While early detection is important, it can also lead to unnecessary biopsies. The 2009 guidelines of the U.S. Preventive Services Task Force (USPSTF) do not recommend screening for the general population. However, those recommendations are being reexamined.

Since the USPSTF guidelines were published, studies have found that physicians tend to detect melanomas at an earlier stage than with home exams. The American Cancer Society and the American Academy of Dermatology recommend regular skin exams for people at higher risk for melanoma.

You should discuss your melanoma risk with your healthcare provider and decide if regular melanoma screening is right for you.

Physical Exam and Biopsy

Melanoma diagnosis starts with a physical exam, during which a healthcare practitioner takes your medical history and looks at your skin for signs of melanoma. These include skin lesions that have an unusual shape, size or color. Your lymph nodes will also be examined to look for signs that melanoma may have spread.

If your healthcare provider thinks that a lesion is suspicious, it will be biopsied. A pathologist will exam the biopsied skin under a microscope to determine if it is melanoma. If it appears the melanoma has spread, you may need a biopsy of nearby lymph nodes as well.

For more detail, see the section on Biopsies and examination of tissues in the Anatomic Pathology feature article.

Laboratory Tests

Laboratory testing may include one or more genetic tests.

Genetic testing for prognosis:
There is a test looks at 31 genes to predict if stage I or II melanoma tumors are at risk of spreading (DecisionDx-Melanoma). However, the National Comprehensive Cancer Network's 2014 guidelines do not recommend molecular prognostic testing outside of clinical trials.

Genetic tests to determine treatment:
New treatments for late-stage melanoma target specific chemical pathways that cancer cells need to grow. These targeted treatments are based on knowledge of the genetic abnormalities underlying melanoma. There are multiple genetic mutations associated with melanoma.

Researchers have developed specialized drugs that shrink melanomas by blocking these pathways. If you have advanced melanoma, you may be tested to learn if you have the following mutations:

• BRAF – Mutations in the BRAF gene are found in more than 50% of melanomas. These mutations are associated with a favorable response to the drugs vemurafenib, dabrafenib, and trametinib in individuals with advanced melanoma. A healthcare practitioner will use the presence of this mutation to determine if someone will benefit from therapies that target the BRAF gene.
• C-KIT – Mutations in the C-KIT gene are more likely associated with melanomas that start in the palms, soles of the feet, or under fingernails. C-KIT mutations are less common than BRAF mutations. As many as 15% of people with melanoma have the C-KIT gene. Therapies are being testing in clinical trials.
• GNA11/GNAQ – Mutations of the GNA11 and GNAQ genes occur in 2% of people with melanoma. Tumors associated with these mutations occur in the eye. While there are tests available for these mutations, there are currently no FDA-approved drugs that target them.
• CDK4 – About 5% of people with melanoma have an abnormal CDK4 gene. There are currently no FDA-approved therapies to target it. However, if someone tests positive for this mutation, there are clinical trials for drugs targeting CDK4.

Genetic testing for melanoma risk:

• Melanoma hereditary cancer panel – This genetic test is usually given as a panel to screen for mutations in the six genes associated with melanoma. The CDK4 gene is most often associated with hereditary melanoma.

A positive result indicates that the person has a genetic mutation associated with increased risk for melanoma. However, a negative test result does not rule out the presence of other genetic abnormalities that could increase cancer risk. Only about half of people with hereditary melanoma carry the genes detected by this test. Researchers have yet to identify every gene, or gene combination, that increases melanoma risk.

Screening for melanoma risk is currently only recommended for certain high risk individuals, including those with a personal history of three or more primary melanomas, a personal history of melanoma and pancreatic cancer, or three or more cases of melanoma and/or pancreatic cancer in first-degree relatives.

If you choose to be tested for melanoma-associated mutations, it is important that you seek guidance from a genetic counselor.

Non-genetic lab testing:

• Serum S-100 protein – In people with melanoma stage III and later, elevated levels of this protein may indicate a greater spread of melanoma and risk of relapse. However, this test is not widely used and not included in staging guidelines.

Melanoma is divided into five stages that describe the tumor's thickness and whether it is ulcerated (open and red or blistered) and how far the cancer has spread. Generally, the cancer has spread more at higher stages. A healthcare practitioner will determine the cancer's stage with physical exams, biopsies, and imaging studies. Staging is important in determining prognosis, treatment, and monitoring for melanoma.

• Stage 0: The tumor is in the epidermis but has not spread deeper than the skin's top layer.
• Stage I: The tumor is less than 1.0 mm thick or between 1 and 2mm thick and not ulcerated; it has not spread beyond the skin to lymph nodes or distant organs.
• Stage II: The tumor is 1-2 mm thick with ulceration or larger with or without ulceration but has not spread beyond the skin to lymph nodes or distant organs.
• Stage III: The tumor may be any thickness, with or without ulceration, and has spread to nearby lymph nodes, or it has spread to nearby skin (satellite tumors) or lymphatic channels near the original tumor. There is no distant spread.
• Stage IV: The tumor has spread beyond the original area of skin and nearby lymph nodes to other organs such as the lung, liver, or brain, or to distant areas of the skin, deeper tissue, or distant lymph nodes.