Melanoma is a form of skin cancer that arises from melanocytes, the skin cells that are responsible for the pigment of our skin. Melanoma is the sixth most common cancer in the United States and the incidence is increasing faster than that of any other cancer. There are approximately 160,000 new cases of melanoma worldwide and 40,000 deaths every year, but only represents 1.5% of all newly diagnosed cancers. The incidence is highest in Australia and New Zealand, followed by North America.
Symptoms of melanoma
The diagnosis is suggested based upon the appearance of a skin lesion. Abnormal findings are described by dermatologists using the acronym ABCDE:
A – Asymmetry (one side is different from opposite side)
B – Border irregularities (jagged, uneven edge)
C – Color variegation (different colons within the same region)
D – Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended)
E – Evolution (change) in color, shape or symptoms over time
Other abnormal features include inflammation (swelling), ulceration, bleeding or crusting. A person who notices any of these changes should contact their healthcare provider as soon as possible. If warranted, referral to a dermatologist is made and biopsy may be necessary to determine if the abnormality is melanoma.
Risk factors of melanoma
Melanoma occurs more frequently in young and middle-aged patients and occurs equally among men and women in these age groups. However, with age the rate of diagnosis increases much more in men than in women, with an approximate 3:1 ratio. The incidence is highest in those of European origin, who have comparatively unpigmented skin. The risk of melanoma is higher in those with fair skin, red or blonde hair and blue eyes. Familial forms of melanoma have also been described.
Studies have suggested that melanoma is linked to sun exposure. This is suggested by the observations that the incidence is highest in European populations living in areas with high levels of ambient solar radiation, with the lowest incidence being in darker-skinned people of African or Asian origin. In addition, personal history of sun exposure also appears to be correlated with development of melanoma. Melanomas tend to occur on the sun-exposed surfaces of the skin, such as the head, face and extremities. Studies suggest that intermittent (generally recreational) sun exposure leads to higher risk of melanoma than continuous (generally occupational) sun exposure. This is supported by the higher incidence of melanoma in patients whom have had frequent and/or severe sunburns.
How is melanoma diagnosed?
Melanoma is diagnosed based on a biopsy of a suspicious skin lesion. Once melanoma is diagnosed, the next step is to determine the extent of disease. This is referred to as “staging” and is important in determining the appropriate treatment. Staging takes into account the thickness of the tumor, presences of absence of ulceration, involvement of nearby lymph nodes, and the presence of tumor spread beyond the lymph nodes (metastases). Initial staging is usually performed with a thorough physical exam, blood tests and a chest x-ray. Additional exams such as a CT scan may be recommended in those with advanced melanoma, history of previous melanoma and those with signs of symptoms of distant metastasis. The staging of malignant melanoma is a description (numbers 0 to IV) of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to (if any) and whether it has spread to distant organs. Staging of cancer is the most important predictor of survival, and cancer treatment is primarily determined by staging.
Treatment Options for Melanoma at Tufts MC
In most patients the primary treatment for melanoma is complete surgical resection of the tumor. This is usually performed using a wide local excision, where 1-2 cm of the surrounding normal skin is also removed to reduce the risk of the tumor recurring at the same site. Surgery is typically performed under local anesthesia and does not require overnight stay in the hospital.
For melanoma located on the head, neck, hands or feet, a tissue sparing approach of staged excision with complete margin exam is offered to minimize the amount of tissue removed while still clearing all the melanoma cells. The melanoma is removed by the surgeon and examined by the pathologist, with results available the next day. If there is residual melanoma, the surgeon will remove additional tissues as needed. If there is no melanoma left, the surgeon will then repair the resulting wound. If a large wound requires extensive reconstruction by plastic, or head and neck surgeons, the removal and reconstruction procedures can be scheduled on the same day for patient's convenience and comfort.
If an enlarged lymph node is present at the time of surgery, it may be biopsied. In the majority of cases, enlarged lymph nodes are not visible. If the melanoma has high-risk features such as ulceration, or if the tumor extends deep into the layers of the skin, further evaluation for involvement of regional lymph nodes is typically recommended with a surgical technique known as sentinel lymph node (SLN) biopsy. This procedure typically is performed under general anesthesia and involves injecting a dye or radioactive material to help identify the lymph nodes that directly drain the area around the tumor. If the SLN biopsy shows evidence that cancer has spread, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes in the area.
Melanoma Adjuvant Therapy
The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.
Interferon alpha (IFNa) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Interferon is a form of immunotherapy that is aimed at boosting the patient’s immune response so that it can more effectively fight the cancer. Treatment begins after surgery and continues for up to 12 months. It is given either subcutaneously or intravenously, and the optimum method of delivery and schedule of treatment are not clear.
Metastatic melanoma refers to patients with stage IV disease, where the melanoma has spread to the local area and into other areas or organs. The most common sites of metastases are the skin, lymph nodes, lungs, liver, brain and bone. The treatment of advanced melanoma focuses on shrinking or getting rid of metastases, preventing the disease from spreading and maintaining or improving quality of life. In most cases, it is not possible to completely eliminate or cure the cancer. Depending upon where and how big the metastases are, treatment may involve medical treatments (chemotherapy or immunotherapy), surgery, or radiation therapy.
Chemotherapy drugs commonly used for melanoma include dacarbazine (DTIC) and temozolomide.
- DTIC is considered the most active chemotherapy drug for metastatic melanoma, efficacy is limited and most patients only respond partially and the benefit lasts only four to six months. DTIC is given intravenously over one hour for five days in a row every three weeks. Nausea and vomiting are the most common side effects, and anti-nausea medications are typically given to reduce or prevent this.
- Temozolomide is an oral medication with limited activity in melanoma, and is most commonly used in patients with metastases to the brain. This is due to the fact that Temozolomide crosses the blood-brain barrier and penetrates into the nervous system, while other treatments do not.
Immunotherapy is currently the preferred front-line treatment for metastatic melanoma. Interleukin-2 (IL-2) is currently the only potentially curative treatment for metastatic melanoma. However, IL-2 treatment has serious and even life-threatening side effects and is generally reserved for people who are otherwise healthy. It is given intravenous and patients are typically observed in the hospital during treatment. Interferon alpha is another form of immunotherapy that is used in patients with advanced or metastatic melanoma.
In 2010, a scientific study was completed using Ipilimumab, a human monoclonal antibody directed against T-cells, in patients with metastatic melanoma. Ipilimumab targets the immune system in an attempt to reverse “tolerance” of the patient’s immune system to the tumor and therefore induce “rejection” of the tumor. The study concluded that Ipilimumab was able to prolong the survival of patients with metastatic melanoma. This treatment also carried the possibility of significant side effects, termed autoimmune-related adverse events (ARAEs). The most common side effect was colitis, an inflammation of the colon leading to diarrhea, which may be bloody and life threatening. Treatment was discontinued in patients who developed AREAs that were severe or persistent.
Research + Clinical Trials
This phase II trial studies the good and bad effects of the combination of drugs called cabozantinib and nivolumab in treating patients with melanoma or squamous cell head and neck cancer that has spread to other places in the body (advanced). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial may help doctors determine how quickly patients can be divided into groups based on biomarkers in their tumors. A biomarker is a biological molecule found in the blood, other body fluids, or in tissues that is a sign of a normal or abnormal process or a sign of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. The two biomarkers that this trial is studying are "tumor mutational burden" and "tumor inflammation signature." Another purpose of this trial is to help doctors learn if cabozantinib and nivolumab shrink or stabilize the cancer, and whether patients respond differently to the combination depending on the status of the biomarkers.
More information about research and clinical trials