Melanoma begins in skin cells called melanocytes. Melanocytes make a pigment called melanin, which protects skin from the sun. They also produce moles, which are usually harmless but occasionally can become cancerous. A melanoma can look like a mole. It is usually brown or black but can also be skin-colored, purple, blue, red, pink, or white. Knowing the difference between a normal mole and a cancerous one, doing regular skin self-exams, and visiting a dermatologist for skin checks on a regular schedule can all be lifesaving. (1)
How Does Metastatic Melanoma Differ From Melanoma?
Melanoma is any cancer that originates in the melanocytes, while metastatic melanoma is melanoma that spreads from the skin to other parts of the body, such as the lymph nodes, liver, lungs, bones, and brain. Most people who develop melanoma — around 4 in 5 — get their diagnosis at an early stage, while the cancer is still localized to the skin. Treatment at this point is straightforward (a doctor may simply cut the tumor out) and extremely effective, with a five-year survival rate of over 98 percent. Metastatic melanoma is much harder to treat and more life-threatening. Overall, melanoma kills more than 7,000 people in the United States each year, according to the National Cancer Institute. (2) Ultraviolet (UV) Light Exposure Whether it comes from the sun or from tanning beds, UV light is a very significant risk factor for melanoma. UV light damages the genes in melanocytes that control their growth. These genetic mutations (changes) direct the cells to multiply with abnormal speed, forming tumors. Blistering sunburns in early childhood are especially dangerous. (3) Moles Certain kinds of atypical moles known as dysplastic nevi, which can be larger than regular moles and have an abnormal shape or color, raise melanoma risk. People with an inherited condition called dysplastic nevus syndrome, which causes them to have many dysplastic nevi, are at very high risk of melanoma. Congenital melanocytic nevi — moles present at birth, especially very large ones — are another risk factor. Fair Skin, Freckling, and Light Hair Individuals with this kind of coloring are at higher risk than other racial groups. Family History of Melanoma Around 10 percent of people with melanoma have a first-degree family member with the disease, such as a parent, sibling, or children. Personal History of Melanoma or Other Skin Cancers Having had melanoma raises the risk of getting it again. Having another type of skin cancer, such as basal or squamous cell skin cancer, is also a risk factor. Having a Weakened Immune System People with conditions that weaken the immune system, such as HIV, are at higher risk of developing melanoma. People taking medication to suppress the immune system after an organ transplant are also at higher risk. Being Older Older people are more likely to develop melanoma than younger people. But younger people are also at risk. In fact, melanoma is one of the most common cancers in people below the age of 30. Gender Men in the United States are at higher risk of developing melanoma than women after age 50. Before age 50, women are at greater risk. Xeroderma Pigmentosum People with this rare inherited condition, which makes people very sensitive to sunlight, have a very high melanoma risk. (4) They may be concerned about a mole that is painful, itchy, or bleeding; that oozes or becomes scaly or lumpy; or that shows other troubling signs. Doctors looks for evidence of cancer in moles using what’s called the ABCDE method:
A It is asymmetrical.B It has an irregular border.C It contains more than one color or is an unusual color.D Its diameter is unusually big (typically larger than 6 mm or ¼ of an inch).E It evolves, changing size, color, shape, or another characteristic.
These are all traits that distinguish a cancerous mole from a benign one. (5) It’s possible that by the time a physician diagnoses melanoma on the skin, cancer cells have already spread to other parts of the body. Melanoma can also spread to a different part of the body after initial diagnosis and treatment. People with metastatic melanoma may feel tired or unwell in general. They also may have specific symptoms based on where in the body the cancer cells have spread. (Some of these symptoms may have noncancerous causes.) Some parts of the body that may be affected by metastatic melanoma include:
Lymph Nodes
Symptoms of melanoma that has spread to the lymph nodes may include:
Hard lumps under the skinDifficulty swallowing (because of swollen lymph nodes in the neck)Swelling in the neck or face (because of fluid buildup, a condition called lymphedema)
Lungs
Melanoma that has spread to the lungs can cause the following symptoms:
A persistent coughBreathlessnessOngoing chest infectionsCoughing up bloodFluid buildup between the chest wall and the lung
Liver
Metastatic melanoma in the liver can cause:
Discomfort or pain on the right side of the abdomenPoor appetite and weight lossAbdominal swellingYellowing of the skin and eyes (jaundice)Itchy skin
Bone
The following symptoms may indicate metastatic melanoma:
Gnawing pain (caused by the breakdown of bone)Worsening backacheWeaker bones that break more easilyRaised blood calcium, which can cause dehydration, confusion, abdominal pain, and constipationLow levels of blood cells (which are produced in healthy bone but crowded out by cancer cells), which can cause bruising, bleeding, and an increased risk of infection
Brain
Melanoma that has spread to the brain can cause:
HeadachesMuscle weaknessSeizuresPersonality or mood changesEyesight changesConfusion (6)
The physician may also feel the lymph nodes under the skin in the neck, underarm, groin, or behind the knees near the abnormal area to check for any unusual enlargement. The doctor will also likely take a skin sample from the unusual area that can be studied under a microscope for cancer cells. If the lab results confirm melanoma, physicians may take samples of other tissues, too, to check for metastases, often starting with the lymph nodes nearest the primary skin lesion. Imaging tests, such as X-rays or computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans, can also look for enlarged lymph nodes or cancerous spots on the lungs, liver, and other body parts. In rare cases, melanoma metastasizes quickly, before the original tumor on the skin is large enough to be detected. In these cases, physicians may first biopsy tissue from an area of metastasis to figure out what type of cancer the patient has. For instance, a biopsy may determine that cancerous spots on the liver are not liver cancer (cancer that originates in liver cells) but skin melanoma that has metastasized. This is critical information, since different types of cancer require different treatment. (7) For patients with metastatic disease, determining the stage is crucial for identifying those who are likely to benefit from certain next-gen treatments.
Stage 0
The melanoma is confined to the outermost layer of the skin; it has not spread.
Stage 1
The melanoma has grown more than 2 millimeters (mm) into the skin but it has not spread. There may be ulceration (breakdown of the skin over the tumor, a danger sign), but it is not a required criteria for this stage of melanoma.
Stage 2
There is still no evidence of metastasis. The cancer is more than 1 mm thick and ulcerated, or more than 2 mm thick with or without ulceration.
Stage 3
The melanoma has spread, sometimes as far as the nearest lymph nodes, but no further. There are a number of stage 3 substages, based on how thick the tumor is, whether or not it’s ulcerated, and how far it has spread. Stage 3A
The tumor is no more than 2 mm thick and may or may not be ulcerated. It has spread to up to three lymph nodes, but is so small it can be seen only under a microscope.
Stage 3B
There is no sign of the primary cancer, and either the melanoma has spread to only one lymph node or it has spread to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor.The cancer is no more than 4 mm thick and it may or may not be ulcerated. Additionally, either it has spread to only one lymph node; to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor; or to two or three lymph nodes.
Stage 3C
There is no sign of the primary cancer. Additionally, either it has spread to one or more lymph nodes; to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor; or to any lymph nodes that are clumped together.The cancer is no more than 4 mm thick and it may or may not be ulcerated. Additionally, either it has spread to one or more lymph nodes; to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor; or to lymph nodes that are clumped together.The cancer is between 2.1 and 4 mm thick; or it is thicker than 4 mm. It may or may not be ulcerated. Additionally, either it has spread to one or more lymph nodes; to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor; or to lymph nodes that are clumped together.The cancer is thicker than 4 mm and is ulcerated. Additionally, either it has spread to no more than three lymph nodes; or to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor.
Stage 3D
The cancer is thicker than 4 mm and is ulcerated. Additionally, either it has spread to four or more lymph nodes; or to very small areas of nearby skin (satellite tumors) or skin lymphatic channels around the tumor; or to lymph nodes that are clumped together.
Stage 4
The cancer can be any thickness and may or may not be ulcerated. It may or may not have spread to lymph nodes. However, the cancer has spread to distant lymph nodes or organs such as the lungs, liver, or brain. (8) But newer types of treatment are proving to be so much more effective that they are replacing chemotherapy as the go-to approach.
Immunotherapy
By harnessing the power of the body’s own immune system to fight disease, immunotherapy has become a game-changer in the treatment of metastatic melanoma. One especially promising type of immunotherapy is called immune checkpoint blockade therapy or immune checkpoint inhibitor therapy. These drugs, which began receiving U.S. Food and Drug Administration (FDA) approval in 2011, are significantly extending the lives of people with stage 3 and stage 4 melanomas and were also approved for the management of high-risk stage 2 melanomas in 2021. Pembrolizumab (Keytruda) and nivolumab (Opdivo), both approved by the FDA in 2014, have become frontline medication for metastatic melanoma. Both work by blocking the action of a molecule called PD-1 (programmed death-1), which normally keeps the immune system’s T cells in check. No longer held back by PD-1, the T cells are let loose to attack cancer. In 2015, President Jimmy Carter credited a combination of surgery, radiation, and Keytruda with sending his cancer into full remission after metastatic melanoma had spread to his brain. (9) A study that followed 655 advanced melanoma patients on Keytruda delivered more promising news. The researchers found that roughly 40 percent of the patients were still alive three years after starting treatment, with 85 patients becoming and remaining cancer-free. (10) Combining different checkpoint blockade therapies can increase the chance of serious side effects, yet researchers are finding that this strategy improves survival so much that the risk might be worth it for some patients. A study involving patients treated with both nivolumab and ipilimumab (Yervoy) found that 52 percent survived for five years or longer.
Targeted Therapies
A new generation of melanoma therapies works by targeting mutations (DNA defects) in melanoma cells, shrinking tumors or slowing their growth. About one-half of all melanomas have mutations (DNA defects) in the BRAF gene that are responsible for out-of-control cellular growth. The FDA has approved several medicines targeting this mutation, called BRAF inhibitors. A combination of these drugs with other drugs aimed at the related MEK mutation has become the frontline treatment for metastatic melanoma with the BRAF mutation. These three combination therapies are now approved:
dabrafenib (Tafinlar) and trametinib (Mekinist)vemurafenib (Zelboraf) and cobimetinib (Cotellic)encorafenib (Braftovi) and binimetinib (Mektovi) (11,12)
But since 2011, physicians have had access to remarkable new drugs that are helping many patients live significantly longer. Many patients with metastatic melanoma are responding to the new treatments, extending their lives by months and years. Some are even going into long-term remission. According to the Melanoma Research Alliance, the five-year survival rate is about 65 percent for stage 3 melanoma and about 20 percent for stage 4. (13) But those numbers are expected to go up now that doctors are treating more and more patients with the new drugs. A 2017 study that focused on patients with stage 4 metastatic melanoma found that new drugs available since 2011 were, in fact, extending lives. Three-year survival for patients who entered stage 4 in 2013 and 2014 was 37 percent, compared with in 2011 (18 percent) and 2012 (20 percent). (14)
