Lauren+Rice

Malignant Melanoma

Apercu: Some treatments may need specific tailoring, but since such a high percentage of melanoma cases are caused by the same mutation, melanoma is rare in that a one size fits all treatment can be effective for the majority of patients. **Part I: Background of Malignant Melanoma** Bob, a 60-year-old white male, has just been diagnosed with malignant melanoma, the most aggressive form of skin cancer. He was born in Hawaii, and currently lives in Southern California. Bob grew up surfing and worked as lifeguard for many years. He is now currently a part-time swim instructor at the local YMCA. He still enjoys spending time outdoors with his family and still has a passion for surfing.

Recently, he noticed that one of the moles on his back suddenly over a period of two months grew in size and darkened in color. He went to the dermatologist, as he was aware that this is a sign of cancer, and the doctor decided to do an excisional biopsy. This means that the mole was completely removed by cutting into the skin and then stitching up the area. This is a common type of biopsy if melanoma is suspected because it cuts out the entire tumor, whereas incisional biopsies only cut out part of it. Shave biopsies are common if melanoma is not suspected since it only removes the top layer. (2) The excisional biopsy was then examined under a microscope, which allowed the pathologist to draw up a pathology report. Because melanoma was suspected, Bob also had his nearby lymph nodes biopsied, as this is one of the first places that melanoma can spread to. (1) Melanoma is the most aggressive form of skin cancer, compared to basal cell carcinoma and squamous cell carcinoma, which grow slowly and rarely spread to other areas of the body. These cancers, also known as nonmelanoma skin cancers, generally respond to treatment as well. However, malignant melanoma is much more likely to spread, is harder to treat, and is the most fatal of the skin cancers if it’s not caught early. (3) The amount of time that Bob spent in the sun in his youth is what most likely caused this disease. Although he wore sunscreen most of the time, he got a few bad burns in his younger years. These bad sunburns are one of the main risk factors for melanoma. Bob also has blue eyes and blonde hair, which puts him at an increased risk for getting sun burns in the first place. The UV rays from the sun damage the DNA of skin cells. Occasionally, this damage affects the cells ability to grow and divide normally, which is what forms the cancer. Fortunately, because Bob was proactive and went to the dermatologist, the melanoma was caught early, and he is hopeful for a positive prognosis.

Bob’s father also had skin cancer, which puts Bob at a greater risk. Scientists believe that the mutations that cause melanoma might not genetic, but rather genetics influence the susceptibility to sunburns, and family influences time spent outdoors: “The increased risk might be because of a shared family lifestyle of frequent sun exposure, a family tendency to have fair skin, certain gene changes (mutations) that run in a family, or a combination of factors” (2). However, it’s been shown that gene mutations that increase the risk of melanoma are often passed on from generation to generation. Since the mole was on his back, it was more likely to be cancerous, as 1 in 3 melanomas occur on the back. (2)

The dermatologist explains to Bob and his family that being a white male also puts him at higher risk for melanoma, as white people are 20 times more likely to get melanoma than African Americans. This is because of their tendency to get more sunburns: “Whites with red or blond hair, blue or green eyes, or fair skin that freckles or burns easily are at increased risk.” (2) This is because the fairer the skin is, the less melanin there is to absorb the UV light that causes damage to DNA. So people with very fair skin, and characteristics that accompany fair skin, are at a higher risk of getting their DNA damaged by UV light from the sun, or from things like tanning beds. Along with his race, Bob’s age is a risk factor. The average age of a skin cancer diagnosis is 62, and men are at a higher risk than women after the age of 45. (2)

Bob’s melanoma is diagnosed at Stage IIA out of four stages, which is promising since the cancer is still in an early stage. Specifically, this diagnosis means that the tumor is T3a, so it’s between 2.01 mm and 4.0 mm thick without ulceration, meaning it has not broken down the skin over the melanoma. This also means that it is N0 and M0, so it has not spread to any nearby lymph nodes and has not been found in any distant organs. Since it has not spread anywhere else and is not ulcerated, there is a high survival rate for Bob: “The 5-year survival rate is around 81%. The 10-year survival is around 67%” (2). People over 70 generally have shorter survival times, so Bob is not in that category. For melanoma that is ulcerated, metastasized, or spread to nearby lymph nodes, the chances for survival become much less and the treatments are more invasive and intense. Often times, these treatments are so aggressive that they have the possibility of causing other types of cancer.

This diagnosis has worried both him and his family, but they are hopeful for a positive outcome. Using the pathology report, they will work together with the dermatologist to figure out the best plan for treatment options. His awareness and knowledge of the disease is likely what will give him high odds for survival, and the cancer will be treated before it has a chance to spread anywhere else.

**Part II: The Molecular Basis of Melanoma** A unique factor that distinguishes melanoma from other cancers is the fact that many cases are due to one mutation. 63% of cases have to do with a mutation of the BRAF gene (7). When the BRAF gene is mutated, the signaling pathways for growth and differentiation in the cell are turned on and do not turn off. As a result, there is proliferative cell growth, which is one of the hallmarks of cancer. BRAF is a proto-oncogene that is part of the RAF kinases and its function is part of the Ras-Raf-Mek-Erk signal transduction pathway, also known as a MAP kinase pathway that signals cell division (see figure 1).



The mutation that normally occurs in BRAF is a single point mutation in which valine (V) is substituted for glutamic acid (E) at codon 600 (BRAF V600E) (4). This causes elevated levels of BRAF, which in turn, signals more extracellular regulated kinase activity, also known as ERK activity. Some of the main components of the MAP kinase pathway are the Ras proteins. When the BRAF gene is mutated, it changes the structure of the protein. This affects Ras, which leads to uncontrollable transcription that doesn’t stop, forming a tumor. The Ras proteins are turned on by GTPase activity and are turned off by GDPase, which helps regulate the signals. In cancer, including melanoma, the Ras protein is in a constant GTPase state, and therefore stays on and never turns off. This becomes an issue since Ras proteins are involved in cell differentiation, growth, and apoptosis. If they are on all the time, the cell cannot check for DNA damage, which causes the cells to continue replicating with incorrect information. Decreased apoptosis and general deregulation is what leads to metastasis. The MAP kinase, or mitogen activated protein kinase, is crucial for transcription. It’s important to note as well that mutated forms of BRAF can produce immunosuppressive factors, which favor tumor growth as well since the immune system is not able to recognize or attack the tumor.

Mutations in BRAF are not the only basis for melanoma. NRAS is similar to BRAF and when it is mutated, can cause proliferative cell growth as well. This is because it affects the Ras protein as well. Although not as common as a BRAF mutation: “Studies show that mutations in the NRAS gene, which lead to a constantly active NRAS protein, are found in approximately 23% of melanoma patients (7), although recent studies analyzing more patients and using more sensitive techniques suggest that as many as 25% of patients may have an NRAS mutation” (6). Together, mutations in NRAS and BRAF are the cause of most melanomas; however, it is very rare for a melanoma patient to have both mutations, since both proteins are in the same pathway. The mutations in BRAF or NRAS are mutually exclusive, as seen on Tumor Portal (4), with an NRAS mutation being more aggressive with a worse prognosis compared to a BRAF mutation (6).

Angiogenesis, the sprouting of new blood vessels, also plays a role in melanoma. As seen in multiple studies, the melanocytes often produce large amounts of VEGF and bFGF, both of which stimulate the growth of new blood vessels. It’s important to note that VEGF by transformed melanocytes plays a bigger role than the hypoxia-induced VEGF (5). The new blood vessels allow the tumor continue growing, since more oxygen is being supplied to that area. Angiogenesis is also known to provide a route that allows tumor cells to spread to other parts of the body, or metastasize. One way these growth factors can be turned on is through exposure to ultraviolent light:

“Exposure to ultraviolet radiation is known to cause genetic changes in skin, which modulate the cutaneous immune response and increase production of several growth factors. This causes uncontrolled proliferation of melanocytes, which, in turn, dramatically increases the consumption of oxygen and nutrients eventually leading to cell starvation and hypoxia. To fulfill this increasing demand additional vasculature needs to be developed. Thus, to increase the blood supply, the tissue begins to produce a spectrum of growth factors which trigger the process of angiogenesis” (5).

However, the new blood vessels that are a result of hypoxia and VEGF can become distorted and can often cause micro hemorrhaging. Blood can’t flow well, which results in the tumor cells remaining in a state of hypoxia, triggering more VEGF. This positive feedback loop is what allows tumors to keep growing uncontrollably. Angiogenesis is also involved in metastasis. The tumor cells can break into the stromal cells. This allows those cells to start to integrate themselves into the bloodstream, specifically through the new blood vessels formed, which then travel throughout the body. They land somewhere and can start to grow a new tumor. This is what allows the original melanoma tumor to spread to nearby lymph nodes and to other parts of the body as well in the later stages of the disease. Fortunately, since so many melanomas are well understood on a molecular level, it is easier to try specific and targeted treatments to cure the disease.

**Part III: Treatments for Melanoma** The effectiveness of malignant melanoma treatments varies depending on the stage of the cancer. When caught early, the five-year life expectancy rate can be very high, but once it is in the late stages or has metastasized, survival rates drop quickly since the cancer is so aggressive. Fortunately for Bob, his melanoma was diagnosed at Stage IIA, so treating his cancer will likely be successful. At stage IIA, the tumor has not spread to other parts of the body. This means that doctors will just be focusing on the main tumor found on his back. The most common form of treatment for this stage of cancer is surgery. Doctors use wide excision to completely remove the tumor from the skin (9). The amount of normal, non-cancer skin removed depends on the size and depth of the tumor. From there, patients like Bob have the option of having a sentinel lymph node biopsy as well to ensure that the tumor has not spread to local lymph nodes. This is recommended because when it comes to treating melanoma, catching it early is essential.

For patients not as fortunate as Bob, and who have been diagnosed with a stage III or IV melanoma, treatments become more invasive. Surgery is normally done to remove the main tumor, but the problem is that the cancer has likely metastasized. Lymph node dissection is done as well in order to see if tumors in that location need to be removed as well. If the tumor is under the skin or found in nearby lymph vessels, other treatment options include injecting vaccines straight into the melanoma: “…injections of the T-VEC vaccine (Imlygic), Bacille Calmette-Guerin (BCG) vaccine, interferon, or interleukin-2 (IL-2) directly into the melanoma” (9). Additionally, radiation is used after surgery as an adjuvant therapy, as well as targeted therapy and immunotherapy. If the patient is stage IV, unfortunately it is very hard to cure. At this point, some metastases, or tumors that have spread to other parts of the body, may not be able to be removed with surgery, and therefore can only be treated with targeted therapies.

Recent studies have shown that targeted therapies and immunotherapies are more effective in treating melanomas than chemotherapy. Since so many melanomas are caused by a mutation in the BRAF gene, a targeted therapy that uses a BRAF inhibitor has been shown to be very effective. This medication can be taken orally and has fewer side effects than traditional chemotherapies (10). Vemurafenib is the most common one used, and it works by targeting the specific mutation at amino acid 600. Using programmed cell death, it stops the BRAF protein in the Raf-MEK-ERK pathway, which disrupts the downstream signaling. However, a big issue with BRAF inhibitors is that some patients develop a resistance within the first year (11). When this happens, different targeted therapies can be used to target other pathways. For example, “First-line combination therapy with BRAF and MEK inhibitor therapy may delay or prevent some of the mechanisms” (11).

In addition to targeted therapies, immunotherapies are also used to treat melanoma. Immunotherapy drugs are checkpoint inhibitors, whereas targeted therapies focus on fixing the specific mutation. Immunotherapies can be helpful in patients with melanoma in advanced stages: “…pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) have been shown to help some people with advanced melanoma live longer” (9). However, these can have more serious side effects, including nausea, fatigue, decreased appetite, and skin rash (12), so it’s important to take that into account when going through treatment options. It’s also important to note that immunotherapies have not been shown to cure melanomas; they can only treat them.

One way for patients to have access to other immunotherapies, and other therapies in general is through clinical trials. There are many clinical trials available to patients with melanoma, but it is recommended most to patients with late stage melanomas or melanomas that are reoccurring: “Many studies are now looking at new targeted drugs, immunotherapies, chemotherapy drugs, and combinations of different types of treatments” (9). Melanoma can reoccur in different areas of the body too due to metastases. In order to treat the metastases, doctors have a variety of ways to treat the other tumors. Unfortunately, melanoma can reoccur in almost any organ. Most of the time, it comes back in the lungs, liver, bones, or brain. In these cases, treatments are similar to stage IV treatments. Cancer reoccurring in the brain is the hardest to treat. If there is only one tumor, surgery may be an option, but most likely radiation will be used to treat this kind of tumor. It’s possible that other treatments such as immunotherapies and chemotherapies will be used as well.

For Bob, the best course of treatment will be excision, or surgery. Since it has not spread, surgery will have the least amount of side effects, and removing the tumor on his back will have a short recovery time. If someone has stage III or IV cancer, surgery combined with targeted therapy, such as Vemurafenib, will be effective. The drug “was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of tumor progression in patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation” (13). The side effects are also minimal and involve fatigue and skin photosensitivity, which can be prevented with sunscreen. If a patient had a late stage melanoma and many metastases, going through treatment may not be worth it. There are clinical trials available, as well as immunotherapy options, but side effects become more severe and the prognosis is not very good. The five-year survival rate is 15-20%, so it would be up to the patient whether to proceed forward with treatment or not.

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