Where does melanoma originate?
Melanomas arise through mutations in a type of cell called melanocytes. The starting spot is called the "primary site." Approximately 90 percent of melanomas arise on the skin and are called cutaneous melanomas. These can be subdivided into melanomas arising on skin surfaces exposed continuously to the sun (chronic sun exposure), such as on the head or neck and melanomas arising on skin surfaces exposed only at times to the sun (intermittent sun exposure), such as on the chest or back.
The remainder of melanomas arise behind the eyes (ocular or uveal melanomas) or lining surfaces such as the sinuses, vagina, or inside the mouth (mucosal melanoma). Melanomas arising on non-hair bearing skin such as palms, soles of feet, or fingernails are called acral melanomas. Approximately 5 percent of the time a primary site cannot be found and this is called melanoma of unknown origin.
The chance of a melanoma having certain mutations in the DNA depends in part on the location of the primary site.
How do you classify melanomas?
Melanomas are classified by stage, from early (stage I, stage II) to advanced (stage III, stage IV). Early stage melanomas are localized to the primary site, while later stage melanomas have metastasized (spread) to other parts of the body. In stage III melanoma the cancer has spread to the draining lymph glands, while in stage IV melanoma the cancer has spread distantly throughout the body via the lymph system and the blood.
Several factors are considered when classifying melanomas, including their histology (microscopic structure), location, and molecular abnormalities (see “What are the causes of melanomas?” below). Early stage melanomas also have further sub-classifications within each stage.
What features of the melanoma affect staging?
Stage I and stage II melanomas are characterized by how deeply into the skin the melanoma has invaded (the Breslow thickness). Thin melanomas invade less than 1 mm while deep melanomas invade more than 4 mm. The deeper the Breslow thickness the worse the prognosis. Thin melanomas also have a worse prognosis if cells undergoing division (mitoses) are present. The presence of ulceration at the primary site (determined by a pathologist) also worsens the prognosis.
Stage III melanomas are subdivided into 3 groups: stage III A, III B, and III C with progressively worsening prognosis. These subdivisions are based on the presence or absence of ulceration at the primary site, the number of lymph nodes involved, and the size of the involved lymph nodes (enlarged or not enlarged, meaning macroscopic or microscopic lymph nodes). If multiple lymph nodes are involved the prognosis is worse.
Stage IV melanoma is subdivided into stage IV A, IV B, or IV C with progressively worsening prognosis. Stage IV A involves spread to the skin, soft tissues below the skin, or distant lymph nodes. Stage III B involves the lungs. Stage III C involves spread to other parts of the body such as the bone, liver, or brain. If a blood test called the LDH is increased in the setting of distant spread, the staging is IV C regardless of the specific locations of spread.
What are the causes of melanomas?
Sun exposure, hereditary factors, and the immune system are all factors in melanoma. Both UVA and UVB rays from sunlight, as well as tanning beds/booths, can contribute to skin cancer and melanoma. Those who have a family history of melanoma (a first-degree relative such as a mother, father, or sibling) are at higher risk. Some melanoma patients have a mutation in a gene known as BRAF or a gene called p53. Those with a compromised immune system, or who have had a previous diagnosis of melanoma or other skin cancer, may also be at higher risk of developing melanomas.
How does the immune system modulate melanoma?
A healthy immune system enables the body to fight off infections and foreign invaders including viruses, bacteria, and other organisms. Cancers, which begin as normal cells that have developed abnormally and multiplied uncontrollably, are more difficult for the immune system to distinguish from healthy cells. As the cancer develops and multiplies, the cells show markers known as antigens. The body can send a signal directing immune cells to the cancer cells, triggering the immune cells to destroy the multiplying cells. Immunotherapy is a way of stimulating the body’s immune system to attack and destroy malignant tumors.
What are the current FDA-approved treatments for the different stages of melanoma?
Early stage (localized) melanomas are often treated with surgery usually with wide excisions. More advanced melanomas may require regional lymph node dissection (if the sentinel lymph node is involved), radiation therapy, and interferon alfa, an immune therapy approved by the FDA for stage II melanomas with invasion of more than 4 mm or for stage III melanomas. For patients with stage IV melanoma, there are four FDA-approved therapies: Dacarbazine, high-dose Interleukin 2 (IL-2), Vemurafenib (zelboraf), and Ipilumimab (yervoy).
How effective are the FDA-approved therapies for stage IV melanoma?
1. Dacarbazine is a chemotherapy administered by vein once every three weeks. Under 20 percent of people receiving this treatment develop shrinkage of the melanoma. This treatment has not been shown to improve lifespan.
2. High-dose IL2 is an immune therapy administered by vein and requiring hospitalization. Excellent heart and lung function are needed to safely receive this therapy. Only 16 percent of people with melanoma who receive this treatment develop shrinkage of tumor but approximately five percent of people develop complete shrinkage where the melanoma may not have returned years later.
3. Vemurafenib is a targeted therapy that blocks the activity of a protein called BRAF. BRAF is mutated in approximately 50 percent of melanomas. Mutations in BRAF cause melanomas to grow. Blocking BRAF kills melanomas. Vemurafenib is a pill taken daily at home twice a day. The response rate is very high with approximately 50 percent of people with melanoma developing shrinkage of tumor. On average the lifespan is greater in people with melanoma expressing a V600E BRAF mutation who receive this treatment over those who don’t. However melanomas find ways to become resistant to the treatment and therefore on average melanomas start growing again in approximately six months (but can be much sooner or later).
4. Ipilimumab is an immune treatment that blocks a protein called CTLA4, which is present on immune cells. This prevents suppressor T Cells (part of immune system) from working. As such the immune system is more active to try to kill melanoma throughout your body. As an analogy, when one has a virus the immune system is activated to fight the virus. When the immune system did its job the protein CTLA4 is expressed causing the suppressor T cells to work better and shut down the immune system. Ipilimumab blocks CTLA4 and prevents this shut down. Treatment with Ipilimumab has been shown to cause a statistically significant average overall survival benefit (which means living longer) when compared to people who did not receive Ipilimumab. The response rate is low but when Ipilimumab works the shrinkage can be very durable.
How should one self-monitor and follow up after a diagnosis and treatment of early stage melanoma?
Those who have been diagnosed with an early stage melanoma and have completed treatment should consult with a medical oncologist in addition to having regular physical examinations and skin examinations. How often you will need to follow up will depend on your particular diagnosis and treatment. Melanoma patients should continue to conduct self-examinations and avoid excessive sun exposure.
What is the role of surgery and sentinel lymph node biopsy in melanoma?
Surgery is an important treatment to remove or excise the melanoma completely. Wide excision with clean margins or negative margins offers the best clinical outcome for patients before the melanoma spreads or develops metastases. An early stage or thin melanoma can be cured by surgery. Sometimes operations are also done in advanced stages for palliation and depend on the individual patient’s medical condition. Also important in the surgical management of malignant melanoma, a sentinel lymph node biopsy is often required to identify any spread to regional lymph nodes and to plan a personal melanoma therapy. The biopsy is usually minimally invasive and targets the main lymph node(s) that may harbor metastatic disease.