by Dr. C.H. Weaver M.D. 6/2022
Malignant melanoma is predominantly a disease of the skin, but may in rare instances occur at other sites, including the mucous membranes (vulva, vagina, lip, throat, esophagus and perianal region), as well as in the eye (uvea and retina). Melanoma arises from melanocytes, which are cells located in the upper layer of the skin that are responsible for producing pigment (skin color). Most melanomas are dark in color (black/brown) because they contain pigment; however, some melanomas do not contain pigment. These are referred to as an amelanotic malignant melanoma and are very difficult to diagnose.
Since the majority of patients enrolled in clinical trials have skin melanoma, this treatment overview will focus on that type of melanoma. It is important to realize that the treatment principles derived from clinical trials involving patients with skin melanoma are applicable to melanomas of the vulva, vagina, male genitalia or anal-rectal areas but, in general, melanomas in these sites have a worse prognosis than skin melanomas.
Melanoma occurs predominantly in adults and 54,000 individuals are diagnosed each year in the United States. The incidence of melanoma of the skin appears to be on a steady rise throughout the world due to increased ultraviolet exposure from the sun and possibly tanning beds. In the United States, researchers have estimated that there is a 2-3% increase per year in the incidence of cutaneous melanoma.1
Symptoms & Signs of Melanoma
The skin is the body’s largest organ and provides many key bodily functions. The skin protects against heat, sunlight, injury, and infection, helps control body temperature and stores water, fat, and vitamin D. The skin has two main layers are the upper or outer layer called the epidermis and lower or inner layer called the dermis. Skin cancers begin in the cells of the epidermis.1
- Squamous cells are thin, flat cells that form the top layer of the epidermis and can become squamous cell cancers.
- Basal cells are found that reside under the squamous cells and can develop into basal cell cancers.
- Melanocytes are cells that the skin pigment melanin that gives skin its natural color. When skin is exposed to the sun or artificial light, melanocytes make more pigment and cause the skin to darken. Cancers that arise from the melanocytes are referred to as malignant melanoma.
Signs of Melanoma
The signs and symptoms for melanoma most commonly include a change in the way a mole or pigmented area of the skin appears. A change in skin appearance is not always caused by melanoma or other skin cancers but should always be brought to the attention of your doctor. The most common signs and symptoms for melanoma are:
A pre-existing mole that:
- changes in size, shape or color
- has or develops irregular borders
- is more than one color
- bleeds or oozes any fluid
- is asymmetrical
- mole that grows near an existing mole
- change in pigmentation (color) of the skin
How to Do a Skin Self-Exam
Your doctor or nurse may suggest that you do a regular skin self-exam to check for skin cancer, including melanoma.
The best time to do this exam is after a shower or bath. You should check your skin in a room with plenty of light. You should use a full-length mirror and a hand-held mirror. It’s best to begin by learning where your birthmarks, moles, and other marks are and their usual look and feel.2
Check for anything new:
- New mole (that looks different from your other moles)
- New red or darker color flaky patch that may be a little raised
- New flesh-colored firm bump
- Change in the size, shape, color, or feel of a mole
- Sore that does not heal
Check yourself from head to toe. Don’t forget to check your back, scalp, genital area, and between your buttocks.
- Look at your face, neck, ears, and scalp. You may want to use a comb or a blow dryer to move your hair so that you can see better. You also may want to have a relative or friend check through your hair. It may be hard to check your scalp by yourself.
- Look at the front and back of your body in the mirror. Then, raise your arms and look at your left and right sides.
- Bend your elbows. Look carefully at your fingernails, palms, forearms (including the undersides), and upper arms.
- Examine the back, front, and sides of your legs. Also look around your genital area and between your buttocks.
- Sit and closely examine your feet, including your toenails, your soles, and the spaces between your toes.
By checking your skin regularly, you will learn what is normal for you. It may be helpful to record the dates of your skin exams and to write notes about the way your skin looks. If your doctor has taken photos of your skin, you can compare your skin to the photos to help check for changes. If you find anything unusual, see your doctor.
Diagnosis & Tests for Melanoma
In order to diagnose a melanoma, a physician will remove the primary cancer and a pathologist will examine the sample under a microscope. Once melanoma is diagnosed, there are three critical factors that need to be determined:
- the thickness of the melanoma
- the genomic profile of the melanoma
- whether or not the melanoma has spread (metastasized) to other parts of the body.
These factors help determine prognosis, treatment and are part of the overall staging evaluation for melanoma. The stage of melanoma is key in order to determine treatment options and outcomes.
Thickness: An important feature of the tumor is the thickness, which is measured in millimeters. Melanoma is divided into 3 groups based on thickness:
- thin melanomas (< 1 mm thickness)
- intermediate melanomas (1 to 4 mm in thickness)
- thick melanomas (> 4 mm).
The thickness of the melanoma is important because it will have an impact on whether the tumor has spread, which is the other critical factor used to determine the stage of disease. The thicker a melanoma is, the more likely it is to have spread to lymph nodes at the time of diagnosis.
Sentinel Lymph Node Biopsy In general, when melanoma spreads, it spreads to lymph nodes near the cancer first. Lymph nodes are small, bean-shaped structures that are part of the immune system. They are found throughout the body and are interconnected by lymph channels. Melanoma tends to spread through lymph channels that drain into lymph nodes in the local area of the primary skin melanoma. Once a pathologist has determined the thickness of the tumor, the next step in pathological staging may involve surgical removal and examination of the local lymph nodes to determine if apparently normal lymph nodes contain melanoma cells.
The sentinel lymph node (SLN) biopsy technique has improved the ability to detect small amounts of melanoma in lymph nodes. A SLN biopsy is a technique that relies on intra-operative lymphatic mapping. During a SLN biopsy, a physician injects a tracer (radioactive isotope and/or blue dye) into the area of the primary melanoma. The tracer, which is taken up by the lymph system, identifies the so-called “sentinel lymph node” which is the first lymph node that could be potentially involved with melanoma. Lymphatic mapping can be performed prior to surgery to aid the physician in determining which lymph node group is the primary drainage basin for any particular area of skin and it can also be used on the day of surgery to identify which lymph node is the first node (sentinel lymph node).
During a SLN biopsy, the physician removes the SLN through a small incision and then a pathologist examines the SLN under the microscope to detect whether or not there is any evidence of melanoma cells. Patients who have a positive sentinel node (melanoma identified) are counseled to undergo removal of all the lymph nodes in the region, while patients who have a negative sentinel node do not undergo further surgery.
There is evidence that surgical removal of involved lymph nodes may improve survival. This may especially be true when only one lymph node is involved with melanoma. Ideally, if there is no melanoma involvement in the lymph nodes, the removal of lymph nodes should be avoided. It is important to know about the presence of local lymph nodes involved with spread of melanoma, as this is one of the criteria frequently used to identify patients at high risk for development of recurrent disease and is also an entry criteria for clinical trials evaluating the role of additional therapy.
Melanoma can spread by local extension (through the lymph system, as described above) and/or by the blood to distant sites. Satellite lesions can also occur in the skin adjacent but separate from the primary melanoma. These are sometimes called in-transit metastases, implying that secondary melanomas have grown in the skin on their way to spreading to local lymph nodes. Any organ can be involved by metastases from malignant melanoma, but the lungs and liver are the most common sites.
In 3-5% of patients, melanoma is present in lymph nodes or other organs without an identifiable primary site and these patients are said to have “melanoma of unknown origin.” In such cases, it is believed that the primary melanoma underwent spontaneous regression, while the metastasis remained. Patients with unknown primary in the lymph nodes or in distant sites have stage III or IV disease and are treated as outlined for malignant melanomas of these stages.
Genomic or Biomarker Testing:
The purpose of looking for biomarkers and genomic alterations in the cancers DNA is to identify targets that can be treated with precision cancer medicines or immunotherapy. Precision cancer medicine utilizes molecular diagnostic and genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Genetic Mutations in Melanoma
Not all melanoma cells are alike. They may differ from one another based on what genes have mutations. Testing for biomarkers or genomic alterations is performed to identify genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific colon cancer cells with specific genetic mutations.3,4
Although BRAF and PD-1 are the most commonly identified biomarkers that direct therapy, several others exist and new ones will be identified over time, hence all patients should undergo NGS testing.
BRAF: The BRAF V600 kinase is a pathway in cells that is active in cellular replication and spread. BRAF V600 mutations (either V600K or V600E) result in unchecked cellular replication and spread, resulting in the growth of cancer cells.3
PD-1: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.4
Staging of Melanoma
Doctors need to determine the stage or the extent of the spread of the cancer. A cancer’s stage is a key factor in determining the best treatment. This requires a number of additional tests beyond the initial biopsy and lymph node evaluation.
- Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than an X-ray.
- Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the tumor.
- Positron emission tomography (PET): Positron emission tomography (PET) scanning has been used to improve the detection of cancer in lymph nodes. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that spontaneously emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
- Bone Scan: A bone scan is used to determine whether cancer has spread to the bones. Prior to a bone scan, a surgeon injects a small amount of radioactive substance into a vein. This substance travels through the bloodstream and collects in areas of abnormal bone growth. An instrument called a scanner measures the radioactivity levels in these areas and records them on x-ray film.
Stages of Melanoma
Patients with melanoma in situ (stage 0) have melanoma cells only in the outer layer of skin (epidermis). There is no invasion of the deeper layer (dermis) and therefore essentially no potential for spread.
Stage I Patients with stage I malignant melanoma have cancer that is found in the outer layer of the skin (epidermis) and/or the upper part of the inner layer of skin (dermis) but has not spread to lymph nodes. The primary melanoma is less than 2 millimeters (1/16 of an inch) thick.
Patients with stage II melanoma have cancer that is 1 to 2 millimeters with ulceration or greater than 2 mm with or without ulceration. Stage II melanoma has spread to the lower part of the inner layer of skin (dermis), but not into the tissue below the dermis or into nearby lymph nodes.
Stage III melanoma includes cancers of any thickness that have spread to the regional lymph nodes. The extent or amount of tumor in the lymph nodes is the most important prognostic factor for patients with stage III melanoma.
Patients with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes or other distant sites in the body, such as the liver, lungs, or brain.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Screening/Prevention of Melanoma
Information about the prevention of cancer and the science of screening appropriate individuals at high-risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable. Skin cancers, which include basal cell carcinoma, squamous cell carcinoma and melanoma, occur more commonly than any other type of cancer. In general, basal cell carcinomas and the most common squamous cell carcinomas are related to chronic sun exposure and are cured by surgical removal. Melanoma is a potentially fatal type of skin cancer that begins in the melanocytes, which are the cells that are responsible for skin color.
The incidence rate of melanoma has been climbing steadily since the early 1970s. In 2003, the American Cancer Society estimated 54,200 cases of melanoma with 7,600 deaths related to the disease. Although melanoma can be successfully cured in its early stages, it is the most common fatal form of skin cancer, accounting for more than 79% of all skin cancer–related deaths. The chance of an individual developing cancer depends on both genetic (inherited) and non-genetic (environmental) factors. Non-genetic or environmental factors may include diet, exercise, or exposure to other substances present in our surroundings. An example of an environmental factor that is known to play a role in facilitating the process of healthy cells turning cancerous is the relationship between tobacco smoking and lung cancers. Other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer. Melanoma results from a combination of environmental factors (exposure to ultraviolet light) and genetic factors.1,2
Heredity or Genetic Factors
Approximately 10% of individuals diagnosed with melanoma have a family history of the disease. The vast majority of these patients have only one or more affected close relatives, which translates to only a small increase in the risk of developing a melanoma. Those at highest risk for developing melanoma are members of rare melanoma-prone families in which there are usually 3 or more affected members in 2 or more generations on the same side of the family. These family members are generally characterized as having multiple melanomas in the setting of dozens of atypical moles. The risk of developing melanoma in members of melanoma-prone families is estimated to be around 50% by age 50. By studying these families, researchers have discovered that the DNA of certain genes is often damaged in melanoma cells. Forty percent of melanoma-prone families have an alteration in the gene, CDKN2A, which is a gene that is normally involved in regulating normal cell growth. Research is ongoing to further define the role of CDKN2A in the development of melanoma.
Xeroderma Pigmentosum (XP): Xeroderma pigmentosum (XP) is a rare, inherited skin disorder characterized by extreme sensitivity to ultraviolet light. Individuals with XP have a genetic defect that prevents the repair of sun-induced damage to DNA. As a result, individuals with XP have a 1000-times higher risk of developing skin cancer than the general population. Almost half of individuals with XP develop a skin cancer by the age of 8 and the condition shortens life expectancy by over 30 years.2
Environmental or Non-Genetic Factors
Although the causes of melanoma are poorly understood, researchers have identified some risk factors that are associated with melanoma.1,2
Moles (Nevi): Most people have moles and most moles are harmless. Generally, moles develop in children and teenagers and increase in size slightly over time to a maximum diameter of 2 mm or so and remain the same size, shape and color for many years. Normal moles are usually evenly colored brown, tan or black spots on the skin that are round or oval and flat or raised. Atypical moles often called “dysplastic nevi” are defined as moles with a diameter of 5 mm or larger, with an irregular shape and variable color. It is not uncommon to have one or several atypical moles over the extremities or truncal regions. However, about 2% of the population is estimated to have Atypical Mole Syndrome (AMS), which is characterized by the presence of large numbers of moles and atypical moles (100 or more) or moles located on unusual sites (ears, scalp, buttocks, or feet). The lifetime risk for developing melanoma in the U.S. population is estimated to be about 1%. Patients with AMS have a slightly increased risk of developing melanoma (6-10%), which is lower than patients who belong to melanoma-prone families.
Melanoma can often be recognized by applying the ABCD rule:
- Asymmetry: The mole is asymmetrical.
- Border Irregularity: The mole has ragged edges.
- Color: The mole is not evenly colored. It may have differing shades of tan brown, black, red, blue or white.
- Diameter: The mole is bigger than 6 millimeters, although some melanomas may be smaller.
A biopsy should be performed on any pigmented lesion that undergoes a change in size, shape or color.
Fair skin: Melanoma is more common in individuals who have fair skin and red or blond hair. With their fair complexions, these individuals tend to burn easily, placing them at a higher risk for developing melanoma. In addition, white people have a 20-times higher risk of developing melanoma than black people because they lack the protective effect of dark skin pigment. However, melanoma can develop in individuals with dark skin.
Ultraviolet (UV) Radiation: UV radiation has been recognized as a major environmental risk factor for melanoma. Sunlight and tanning lamps are sources of ultraviolet radiation. In fact, excessive exposure to the ultraviolet rays of the sun may account for two-thirds of all melanoma cases. Melanoma is more common in individuals who live in areas with greater exposure to UV radiation, such as Australia, New Zealand, Hawaii and California. There has been controversy regarding artificial tanning beds and whether the ultraviolet rays from these beds further increases the risk of melanoma. Several studies have suggested that more than 10 hours of exposure to a sunlamp/sun bed increases the risk of melanoma. However, given the delay between exposure and cancer development this is difficult to prove. The bottom line is that there is good data to suggest that exposure to tanning beds may provide exposure to dangerous levels of UV radiation and that over the next several decades there will be a dramatic increase in melanoma cases related to this hazardous agent.
Weakened Immune System: Individuals with weakened immune systems are at an increased risk of developing melanoma. This includes individuals who have been treated with medicines to suppress the immune system following an organ transplant and individuals who have AIDS or certain types of cancers that weaken the immune system.
Severe Sunburns: Individuals who have had one or more severe, blistering sunburn, especially as a child or teenager, are at an increased risk for developing melanoma. The risk of melanoma is greater for individuals who have had occasional but intense UV exposure than for those who have had consistent but lower level UV exposure, even if the overall UV dose is the same. Although sunburns during adult years are damaging, research indicates that 50-80% of the skin’s lifetime sun damage occurs during childhood or adolescence.
Wealthy Women at Higher Risk of Melanoma: It appears that wealthier White women may be at a higher risk of melanoma than less affluent women. These findings were recently published in the Archives of Dermatology.
Melanoma is the most deadly type of skin cancer. Each year in the United States, there are roughly 68,000 new diagnoses of melanoma and 8,700 deaths from the disease. Melanoma incidence has increased strikingly among young women—during the past three decades rates of the disease have more than doubled among this population.
Wealthier women and girls appear to be at greater risk, possibly due to the large amount of leisure time spent outdoors and frequent use of tanning beds among this group.
To investigate the relationship between socioeconomic status and melanoma incidence among girls and young women, researchers evaluated 3,800 non-Hispanic White girls and women aged 15 to 39 years who had been diagnosed with melanoma. The level of UV exposure in the areas where participants lived was also assessed.
Melanoma incidence appeared to increase most among the highest socioeconomic levels. Though there was an increase across all income levels, the rise was only statistically significant at the top three levels. Levels of UV exposure were also factors: rates of melanoma were 80% higher among women and girls from top socioeconomic categories who lived in neighborhoods with the highest UV exposure than among those from lower socioeconomic and lower UV-exposure categories.
By identifying the increased risk for melanoma among more affluent women and girls who live in areas with high levels of UV exposure, health experts may be able to target this population with educational efforts about the risk of melanoma and how to prevent it.
Reference: Hausauer AK, Susan M. Swetter SM, Cockburn MG, et al. Increases in melanoma among adolescent girls and young women in California: trends by socioeconomic status and UV radiation exposure. Archives of Dermatology[early online publication]. March 21, 2011.
History of Melanoma: The risk of developing a second melanoma in a patient who has had a previous melanoma is estimated to be 3-7% or about 0.25% per year lifetime risk.
Melanoma Rates Increasing in Young Women
Rates of melanoma-the most deadly form of skin cancer-continue to increase among young women in the United States. These results were published in the Journal of Investigative Dermatology.
The three most common types of skin cancer are melanoma, basal cell carcinoma, and squamous cell carcinoma. Melanoma is less common than basal cell or squamous cell skin cancer, but tends to be much more aggressive. Of the more than one million new diagnoses of skin cancer each year, roughly 62,000 involve melanoma. More than 8,000 people die of melanoma each year in the United States. What makes melanoma so dangerous is that it is more likely than other types of skin cancer to spread (metastasize) to other parts of the body. Melanoma can occur anywhere on the body. The first signs of melanoma may be a mole that changes in appearance, bleeds, or has more than one color or an irregular shape.
To explore trends in the incidence of melanoma among young adults in the United States, researchers evaluated information from a large U.S. cancer database: the Surveillance, Epidemiology, and End Results (SEER) Program. The study, which focused on Caucasians between the ages of 15 and 39 years of age, collected information about melanoma diagnoses between 1973 and 2004.
- Among young men, the rate of melanoma increased from 4.7 cases per 100,000 people in 1973 to 7.7 cases per 100,000 people in 2004.
- Among young women, the rate of melanoma increased from 5.5 cases per 100,000 people in 1973 to 13.9 cases per 100,000 people in 2004.
- During the most recent time period, rates of melanoma in young men remained fairly stable, while rates in young women continued to increase.
Although the researchers did not collect information about the reason for the increase in melanoma among young women, they note that the prevalence of sunburns and use of tanning beds also increased during this time period. Exposure to ultraviolet radiation from the sun or from tanning beds increases the risk of skin cancer.
History of Melanoma: The risk of developing a second melanoma in a patient who has had a previous melanoma is estimated to be 3-7% or about 0.25% per year lifetime risk.
Prevention of Melanoma & Skin Cancers
Two-thirds of cancer deaths in the U.S. can be linked to tobacco use, poor diet, obesity, and lack of exercise. All of these factors can be modified. Nevertheless, an awareness of the opportunity to prevent cancer through changes in lifestyle is still under-appreciated. The best way to reduce the risk of developing melanoma is to avoid known risk factors.1,2
Reduce UV Exposure: Two-thirds of melanoma cases are directly associated to UV radiation exposure. In order to reduce the risk of developing melanoma, it is important to limit exposure to UV radiation and avoid severe sunburns. The UV rays of the sun are strongest between 10 a.m. and 3 p.m. One way to reduce exposure to UV radiation is to remain indoors or seek shade during this part of the day. In addition, individuals can protect their skin by covering up with long-sleeved clothing, hats and sunglasses.
Sunscreens with a sun protection factor (SPF) of 15 are considered to be adequate for normal people under most conditions. However, some recommend higher SPFs, such as 20-30, to compensate for uneven application by the typical users. It is important to note that sunscreen only reduces the amount of UV exposure, but does not prevent melanoma altogether. Sunscreen should not be used as an excuse to prolong sun exposure. Individuals who use sunscreen to extend their time in the sun expose themselves to the same amount of UV radiation as if they had remained outside for a shorter period of time without sunscreen.
Artificial tanning devices are best avoided, as a growing body of evidence indicates that they emit UV radiation that can damage the skin and increase the risk of developing melanoma.
Because 50-80% of the skin’s lifetime sun damage occurs during childhood and adolescence, it is imperative that parents take appropriate precautionary measures to adequately protect their children from excessive sun exposure.
Currently, the American Academy of Dermatology recommends the following measures: use of a broad-spectrum sunscreen with an SPF of 15 or greater; use of sunscreens for any sun exposure of more than 20 minutes; application of sunscreens 15 to 30 minutes before sun exposure; particular attention to the face, ears, hands, arms, and areas not covered by clothing; reapplication of sunscreen every 2 hours, using approximately 1 ounce for exposed areas; and use of hats and other protective clothing in addition to sunscreen for adequate protection.
- Cancer Facts & Figures 2017. American Cancer Society website. Available at: .
- National Cancer Institute. What You Need to Know About™ Skin Cancer. NIH Publication 05-1564. Revised June, 2005. Available at: . Accessed December 7, 2006.
- Ascierto P, McArthur G, Dreno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF V600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology. 2016;17 (9): 1248-1260.
- Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for Advanced Melanoma Met Co-Primary Endpoints and Will Be Stopped Early [press release]. Merck website. Available at: . Accessed April 8, 2015.