A melanocyte is a normal cell found in the skin that produces melanin. Melanin is a black or dark brown pigment that is seen in the skin, hair, and parts of the eye. Melanin is transferred from the melanocytes into nearby skin and hair cells. The concentrated areas of color seen on the skin are known as moles or nevi.
Melanoma is a type of cancer that forms from melanocytes. Melanoma is the most serious form of skin cancer and is now the fifth most common cancer in the United States. Even though melanoma accounts for about 5% of all skin cancers, it is responsible for the majority of deaths from skin cancer. Other common types of skin cancer include basal cell carcinoma and squamous cell carcinoma.
In 2013, the American Cancer Society estimates 76,690 new cases of melanoma diagnosed in the United States. The number of new cases of melanoma has steadily increased for the last 30 years. Fortunately, overall death rates have remained relatively stable, reflecting increased survival due to early detection.
Melanoma can occur any place that melanocytes reside. The majority of melanocytes reside in the skin; therefore, the majority of melanomas are found on the surface of the skin, which includes nail beds, soles of the feet, and scalp. However, melanoma can also occur in the eye ("uveal melanoma") or on internal mucosal surfaces, which include the mucous membranes lining the sinuses, the anal canal, rectum, and vagina.
The single most important risk factor for melanoma is exposure to ultraviolet radiation from the sun. Other risk factors for cutaneous melanoma include fair skin or complexion, a history of peeling sunburns, prolonged exposure to ultraviolet light (both sun and artificial UV light), multiple moles, older age, a personal or family history of non-melanoma skin cancer, and a personal or family history of melanoma. As we age, our years of sun exposure increase, and therefore the risk of melanoma increases.
Researchers have found that the risk of melanoma is 2.24 times higher in people with a first-degree relative with the diagnosis; therefore it is important to be aware of your family history. If you have been diagnosed with melanoma, it is important to share this information with your relatives so that they can undergo appropriate screening. While most melanomas do not arise from moles, certain types of moles, called dysplastic nevi, are associated with an increased risk for melanoma. Dysplastic nevi are moles that are typically large (>5mm in diameter), have uneven pigmentation, and irregular borders. A single dysplastic nevi is associated with a 2-fold increased risk, while 10 or more nevi indicate a 12- fold increased risk of developing melanoma.
People with fair skin and light eyes, or those who have a tendency to freckle or burn easily are all at higher risk. Melanoma rates are 20 times higher in Caucasians than in Blacks. The melanin in dark-skinned individuals has been found to have a natural sun protection factor (SPF) and can filter twice as much ultraviolet light as that of a light-skinned individual. This protection, however, is not complete, and melanoma can develop in dark-skinned people. Melanoma is more commonly found on soles, palms, or nail beds in dark-skinned people.
A history of 3 or more sunburns, particularly blistering sunburns, before age 20, greatly increases risk. A history of severe sunburns in childhood and adolescence may actually double the risk of melanoma in adulthood. For many years, the tanning industry has promoted tanning salons as a safe alternative to natural sun because these devices prevent sunburn; however, artificial UV light has definitively been linked with an increased risk of melanoma as well as other types of skin cancer. In fact, women under 35 who have ever used a tanning bed are 50% more likely to develop melanoma than women who never used a tanning bed. The bottom line is that tanned skin, whether from a tanning bed or sunlight, is not healthy and actually indicates that the skin has been damaged.
The best way to prevent melanoma is to protect the skin from exposure to ultraviolet light, which includes natural UV light from the sun and artificial UV light from tanning devices.
Some ways to protect your skin from UV light include:
You should examine your own skin regularly, approximately once a month. Be aware of the shapes and coloring of any moles you have. Melanoma may develop from an existing mole, causing its appearance to change. Examine your skin routinely in a mirror, including your back, bottom of your feet, nail beds, and scalp. Look for changes in existing moles, or the development of new ones.
Concerning moles are ones that have the "ABCDE" characteristics. You should bring any mole with these features to the attention of your health care provider.
These rules are not set in stone, which is why you should be aware of your own moles, and report any changes in moles to a physician
The best screening test is a skin examination. Your physician should examine your skin during routine physicals, but you should also examine your skin routinely at home. Because you see your skin everyday, you are most likely to notice any changes early on. The prognosis for melanoma is best when lesions are found early, making skin examination very important.
Melanoma often presents as an irregular mole on the surface of the skin, with the "ABCDE" characteristics described above. This can be a preexisting mole that has changed or a newly developed mole. However, many melanomas do not possess these features, so any changes in your skin should be brought to the attention of your health care provider. Additionally, more advanced lesions may have inflammation, oozing, crusting, itching, ulceration or bleeding. Sometimes, specialized photography can be utilized to help monitor a person's skin; these pictures can make it easier for both the patient and the health care provider to detect any changes in moles. This can also cut down on unnecessary biopsies by showing stability of moles over time.
Unfortunately, some patients with melanoma do not present with an abnormal skin lesion and the first signs and symptoms of the disease result from metastatic spread to other organs.
When melanoma is suspected, an excisional or an incisional biopsy should be performed. These biopsy techniques are both "full-thickness", removing the lesion and all the layers beneath it, allowing the depth of the lesion to be accurately determined. The depth of the lesion determines prognosis and treatment, so it is important for this to be accurate. An excisional biopsy removes the entire lesion, while an incisional biopsy removes only a portion of the lesion—an incisional biopsy is usually used for very large lesions to confirm the diagnosis before treatment. The alternative is a shave biopsy, which does NOT allow for accurate assessment of lesion depth.
The four most common subtypes of melanoma are:
While acral lentiginous melanoma is the least common in Caucasians, it is the most common form of melanoma in dark-skinned populations and is usually found on the palms, soles or under the nail. In general, the subtype of melanoma is not a major factor in determining prognosis.
Melanoma can also arise in the mucosal surfaces, known as mucosal melanoma (i.e. sinuses, gastrointestinal tract, urinary tract and vagina) and in the eye, known as ocular or choroidal melanoma. The initial surgery and management of these types of melanoma are different than melanomas that occur on the skin.
After the initial biopsy is performed, a pathology report is issued by the dermatopathologist. This pathology report further describes numerous aspects of the melanoma, which help determine the overall prognosis, many of which are highly technical and outside the scope of this article. The most important aspects of the pathology report are the depth of the melanoma, whether or not ulceration is present, and the mitotic count in thin melanomas.
The depth of the melanoma is often referred to as the Breslow depth or thickness. It describes the vertical depth of the melanoma in millimeters. Other measurements that may be included on the pathology report are the Clark's level, which describes the layer of skin involved with melanoma, and the diameter of the melanoma; neither of these measurements impact the staging of melanoma. Be careful not to confuse Clark's level with the stage of melanoma.
After evaluating the features of the primary melanoma, which are reported on the pathology report, a second surgical procedure, called a wide local excision, is typically performed. At the same time, evaluation of the local lymph nodes, through a sentinel lymph node biopsy may also be performed.
Surgery is the mainstay of curative treatment for melanoma. After a melanoma is diagnosed by a biopsy, the next step is to have a "wide local excision". This surgical procedure removes an area of normal tissue around where the lesion was located. The amount of tissue removed is based on the depth of the melanoma. "Margins" refer to the tissue around a tumor, in this case melanoma. "Negative margins" mean a small amount of normal tissue around the entire tumor was also removed—this ensures the entire melanoma is removed. "Positive margins," on the other hand, indicate that melanoma extends all the way to the edge of the tissue removed, and that it is possible some melanoma may not have been removed. The planned surgical margin depends primarily on the Breslow depth and generally range from 0.5 to 2cm.
If the melanoma is deeper than 1mm or has other features associated with a greater risk of recurrence, a sentinel lymph node biopsy may be performed. In a sentinel lymph node biopsy, a blue dye with a radioactive tracer is injected into the site of the original tumor. The dye spreads to the "sentinel node(s)" (the first few nodes to which the cancer would spread). These blue / radioactive lymph nodes are removed, examined under a microscope and tested for cancer. If any of these lymph nodes are positive, the remaining lymph nodes in the region are removed, a procedure known as a lymph node dissection or lymphadenectomy. If the sentinel nodes do not contain melanoma, a lymph node dissection can be avoided and potential complications eliminated.
Staging for melanoma is defined by the American Joint Committee on Cancer (AJCC, 2009) using Breslow Depth as follows:
*Note that you may not always identify the primary skin lesion in Stage III-IV disease. This is known as "melanoma with unknown primary."
Melanoma can also spread into the region between the original site and the lymph nodes. These lesions are called "in-transit metastases." These are often treated with the treatment modalities used in Stage III or IV disease. Patients with stages III-IV require further evaluation for metastases often including CT scans, PET scans, and/or MRI.
In Stages IIB, IIC and III melanoma, the cancer has been removed by the surgery, and there is no evidence of disease on physical examination, laboratory tests, or radiology tests. Unfortunately, there are often tumor cells circulating in the body that we cannot see on scans. For this reason, patients may be offered further treatment with medications or radiation, which is called adjuvant treatment.
Surgery is the mainstay of curative treatment for melanoma. As mentioned above, the initial diagnosis is made following a biopsy. Additional surgeries may include a re-excision of the primary skin lesion, a wide local excision, a sentinel lymph node biopsy, and a completion lymph node dissection.
If melanoma returns, surgery can often be used to remove the sites of recurrent disease. Additionally, surgery can be utilized in advanced melanoma to manage symptoms associated with a particular tumor.
Chemotherapy is the use of chemicals or medications that travel to all tissues throughout the body to kill any cancerous cells. These therapies have an effect on melanoma that can be seen on imaging studies as well as melanoma cells that cannot be seen. Chemotherapy agents commonly used in melanoma treatment include: Dacarbazine, cisplatin, carboplatin, temozolomide, abraxane and paclitaxel.
In melanoma, some of the medications used to treat this condition are considered immunotherapy agents, meaning that they work by stimulating the patient's own immune system into attacking cancer cells. Some immunotherapy agents used in melanoma are interferon, interleukin-2, and ipilimumab.
Interferon alfa has been the mainstay of adjuvant therapy for melanoma (adjuvant therapy is any treatment given along with the primary treatment, in this case surgery, when there is no evidence of melanoma). Interferon alfa is the best studied and has shown to improve disease-free survival in certain patients with Stage II/III melanoma. However, the benefit on overall survival is still unclear and the therapy has side effects that impact quality of life. The two forms of interferon alpha that are utilized in melanoma are Intron-A® and Sylatron®. Sylatron® is a specially formulated form of interferon that is administered once a week.
Interleukin-2 is used to treat advanced or metastatic melanoma. It is administered intravenously in specialized treatment centers. It must be administered in a hospital because of the side effects associated with this therapy.
Ipilimumab, was approved in 2011 for use in the treatment of metastatic or unresectable melanoma. Ipilimumab is a monoclonal antibody therapy, which works to stimulate the immune system to destroy cancer cells. It takes the "brakes" off the immune system, by increasing the number of T-cells. Ipilimumab led to improved survival in people with advanced melanoma. The side effects of this therapy result from this increase in the activity of T-cells in other organs of the body, most commonly the skin, the digestive tract, the liver, or the endocrine system. Good communication with your health care providers is essential when you are receiving this therapy.
As more is learned about the development of melanoma, molecular targets within melanoma cells are being discovered and new therapies are developed to attack these targets. BRAF is a protein kinase that plays a role in regulating the pathways responsible for cell replication and survival. In approximately 50% of melanomas, this protein is altered or mutated. There are therapies that target mutated BRAF and can be utilized in patients with melanoma containing a specific BRAF mutation. These medications only work in melanoma that has a mutated form of BRAF and testing is performed prior to starting therapy to assure that the therapy is appropriate for the patient. To test for mutated BRAF, a sample of the tumor is sent to a special laboratory that performs the test.
There are two medications available that target mutated BRAF. Vemurafenib was approved by the FDA in 2011 and Dabrafenib in 2013. Both of these medications are taken by mouth (orally). Although they target the same protein, the dosing and side effects of these two agents are slightly different. They are both associated with an increased development of squamous cell carcinomas of the skin, EKG changes, and UV sensitivity, among others. Dabrafenib has also been associated with fevers and serious febrile reactions.
MEK is another protein along the same pathway as BRAF. Trametinib is a MEK inhibitor that was approved by the FDA in 2013. It has been shown to be effective in patients with BRAF-mutated melanoma who have not been previously treated with a BRAF inhibitor. It is an oral medication with specific requirements for storage and monitoring. It has been associated with a variety of side effects including cardiac effects, retinal effects, pulmonary effects, and skin toxicities.
Another option for patients with multiple melanoma tumors confined to one limb is isolated limb perfusion (ILP) or isolated limb infusion (ILI). These procedures involve temporarily interrupting circulation to the affected limb and administering high doses of chemotherapy (such as melphalan) to the limb, along with heat. These procedures must be performed under anesthesia in the operating room; they are associated with local side effects, but have limited toxicity to the rest of the body. This is usually reserved for melanoma that is isolated to a single limb and is not amenable to surgical resection. Response rates ILP/ILI are variable. Some studies have shown a benefit to overall survival in those patients who respond completely (no residual disease) to ILP.
Radiation therapy uses high energy x-rays to kill cancer cells and is a localized treatment, meaning it only affects the tissues directly treated with radiation. Radiation is not routinely used to treat all cases of melanoma. However, in Stage III melanoma, radiation therapy has been shown to be beneficial when used to treat areas at high risk for recurrence, such as lymph node basins. In this setting, radiation therapy can help to prevent a recurrence in the area treated with radiation. Additionally, in Stage IV melanoma, radiation may be used to treat distant metastases in the brain and bone, to reduce symptoms related to the disease or to prevent a decline in function.
Stereotactic radiosurgery (SRS, Gammaknife, Cyberknife) is a highly precise form of radiation therapy that is used to treat metastases. Stereotactic radiotherapy delivers radiation from many different angles to focus the radiation at one small point, like a magnifying glass. It is generally given in 1-5 treatments, unlike traditional radiation, which is given daily, over a period of weeks.
Clinical trials play a pivotal role in the treatment of melanoma. There are many new therapies being evaluated in clinical trials for use in various stages of melanoma. Clinical trials provide patients access to these new and exciting therapies. In addition to testing new treatment options for patients, clinical trials also can provide access to the use of new combinations of existing therapies, not previously used together. Clinical trials are also using therapies that have been shown to extend survival in Stage IV melanoma and in Stage III melanoma to determine if earlier use of these agents may reduce the risk for recurrence. Current clinical trials may include: the identification of new targets for melanoma treatment, targeted therapies that work on newly discovered targets in melanoma, vaccines (which can be made from the patient's own tumor cells or parts of melanoma cells), new combinations of chemotherapy and immunotherapy, and new surgical techniques.
New medications and techniques are continually being tested to find more effective therapies for this disease. It is crucial that patients with a diagnosis of stage III or IV melanoma be treated by a melanoma specialist who is well-versed in current treatments, available clinical trials, and works with an interdisciplinary team (radiation, surgery, supportive care services) to manage patients with all available treatments. Patients with Stage IV disease will require regular clinical, laboratory and imaging evaluations to monitor their disease and response to treatment.
After a diagnosis of melanoma, patients remain at risk for the development of a new melanoma or non-melanoma skin cancer and for a recurrence of the previously diagnosed melanoma. Having one melanoma in a patient's lifetime places him/her at higher risk for developing a second melanoma and follow up with a dermatologist is a mainstay of on-going treatment, with a complete skin exam at least once a year. All patients require ongoing follow up with their dermatologist and depending on the stage of the original melanoma, may require ongoing monitoring by their surgeons and medical oncologists.
For most patients diagnosed with Stage I and II melanoma, follow up will consist of clinical full body skin examinations with a dermatologist every 3-12 months for life, the frequency of which depends on the time elapsed since diagnosis. In addition to clinical total body skin exams, patients should perform self skin examinations about once a month, checking for any new or changing skin lesions, looking for the ABCDEs of melanoma risk, and looking for any new lumps or bumps in the area of the prior melanoma. Individuals diagnosed with a melanoma should practice safe sun habits to minimize their risk for developing a second melanoma or non-melanoma skin cancer (Sun Safety Tips) Routine blood and radiology tests are not recommended for stages I-II, but should be performed to investigate any concerning symptoms.
For patients with Stage III melanoma, a clinical full body skin examination should be performed every 3-12 months for life, the frequency of which depends on the time elapsed since diagnosis. In addition to examination of the skin, the lymph nodes should also be examined. Members of the health care team in Stage III patients may consist of a dermatologist, a surgical oncologist, and a medical oncologist. Additionally, some patients with Stage III melanoma may have regular blood work and imaging studies for approximately 5 years following the diagnosis. Blood work may consist of a complete blood count, liver functions tests, metabolic markers, and an LDH (lactate dehydrogenase), as well as other laboratory tests depending on the previous treatment. Radiology testing may include ultrasound, CT scans, or MRI.
For patients with Stage IV melanoma, a clinical full body skin examination should be performed every 3-12 months for life, the frequency of which depends on the time elapsed since diagnosis. In addition to examination of the skin, the lymph nodes and other organ systems should also be examined. Members of the health care team in Stage IV patients may consist of a dermatologist, a surgical oncologist, and a medical oncologist. Additionally, patients with Stage IV melanoma will likely have regular blood work and imaging studies for at least 5 years following the diagnosis. Blood work may consist of a complete blood count, liver functions tests, metabolic markers, and an LDH (lactate dehydrogenase), as well as other laboratory tests depending on the previous treatment. Radiology testing may include ultrasound, CT scans, or MRI.
Melanoma survivors should report any of the following to your healthcare providers:
Cancer survivorship is a relatively new focus of oncology care. With some 13 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers.
This article is meant to give you a better understanding of the basics of melanoma. Use this knowledge when meeting with your physicians, making treatment decisions, and continuing your search for information.