Skin cancer is the most common of all human cancers. In 2020, more than 100,000 people in the U.S. are expected to be diagnosed with some type of the disease. Nearly 7,000 are expected to die. There are three major types of skin cancers: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. Among of them, melanoma accounts for only about 1% of skin cancers but causes a large majority of skin cancer deaths. So what is melanoma? How does melanoma develop? And how to diagnose it?
1. What is Melanoma?
Melanoma, usually referred to as malignant melanoma, is a highly malignant tumor derived from melanocytes which control the pigment in your skin. The figure 1 shows melanoma cells extending from the surface of the skin into the deeper skin layers. Melanoma occurs mostly in the skin, but also in the mucous membrane and viscera, accounting for about 3% of all tumors. Melanoma is the deadliest form of skin cancer and strikes tens of thousands of people around the world each year. The number of cases is rising faster than any other type of solid cancer .
Figure 1. a diagram of melanoma
In 2020, the American Cancer Society's estimates that there will have approximately 100,350 new melanomas diagnosed (about 60,190 in men and 40,160 in women), and 6,850 deaths from melanoma (about 4,610 men and 2,240 women). The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. So how does melanoma develop?
2. How does Melanoma Develop?
Melanoma occurs when something goes wrong in melanocytes, the cells producing the pigment melanin. Normally, skin cells develop in a controlled and orderly way — healthy new cells push older cells toward to the surface of skin, where they die and eventually fall off. But when some cells undergo DNA damage, new cells may start to grow out of control and can eventually form a mass of cancerous cells. So what damages DNA in skin cells?
In fact, it isn't still clear. It may be a combination of factors, including environmental and genetic factors, causes melanoma. Currently, doctors believe exposure to ultraviolet (UV) radiation from the sun and from tanning lamps and beds is the leading cause of melanoma. UV light doesn't cause all melanomas, especially those that occur in places on your body that don't receive exposure to sunlight. This suggests that other factors may contribute to your risk of melanoma. Regarding to the risk factors of melanoma, continuing to read…
3. What are the Risk Factors of Melanoma？
As mentioned previously, exposure to ultraviolet (UV) radiation and other sources of ultraviolet light, like tanning beds, is a very important risk factor. In addition to the ultraviolet light, factors that may increase risk of melanoma include:
- Race. The American Cancer Society states that the lifetime risk of developing melanoma is about 2.6% for white people, 0.1% for Black people and 0.6% for Hispanic people. Accumulating evidence has revealed that melanoma in white people is 20 times more common than black people.
- A family history of melanoma. If a close relative (such as a parent, child or sibling) has had melanoma, you may have a greater chance of developing melanoma.
- Weakened immune system. People with weakened immune systems also have an increased risk of melanoma and other skin cancers. Your immune system may be impaired if you take medicine to suppress the immune system, such as after an organ transplant, or if you have a disease that impairs the immune system, such as AIDS.
- Age. The risk of melanoma grows as you age. The average age at diagnosis is 65, even though it's one of the most common cancers among young adults.
4. What are the Symptoms of Melanoma?
Studies reported that the origin of melanocytes is associated with the fetal period and the melanocyte precursors. The melanocyte precursors are produced in the neural ridge which migrate to various localizations in the body during fetal development, including the skin, meningeal coverings, mucous membrane, the upper part of esophagus, and the eyes. So melanoma can develop by malignant transformation of melanocytes anywhere on your body  . The most likely areas, though, are chest and back for men, legs for women, neck and face, because these areas have more exposure to the sun than other parts of the body.
The first symptoms of melanoma often are changes in an existing mole and the development of a new pigmented or unusual growth on your skin. Clues that a mole might be melanoma are: irregular shape, irregular border, multicolored or uneven coloring, larger than a quarter of an inch, changes in size, shape, or color, itchiness or bleeding. Sometimes, the skin will appear normal even though melanoma has begun to develop.
As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma . In the next section, we illustrate the mechanisms of melanoma as brief.
5. What are the Mechanisms of Melanoma?
Melanoma caused by transformation of melanocytes requires a complex interaction of exogenous and endogenous events. There are tremendous progress has been reported to make in unravelling the genetic basis of melanoma   . As the figure 2a shows, under normal conditions, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3‑kinase (PI3K)–AKT signaling permit balanced control of basic cellular functions, including cell cycle regulation, survival, motility and metabolism.
However, in melanoma, several genetic alterations depicted in the figure 2b are frequently observed, leading to constitutive pathway activation (indicated by thick arrows) and loss of cellular homeostasis. Malignant transformation can require combinations of genetic defects. The functional consequences of genetic events determine whether mutations can coexist or remain mutually exclusive. For example, mutations in NRAS and BRAF occur very rarely in the same melanoma cell, whereas combined genetic alterations of BRAF and PTEN are common.
Figure 2. signaling pathways in melanoma
*this diagram is derived from publication on Nature Reviews .
6. How to Diagnose Melanoma?
There are a series of tests and procedures used to diagnose melanoma, including:
- Physical examination. Your doctor will ask questions about your health history and examine your skin carefully to look for signs (as mentioned on section 4) that may indicate melanoma.
- Blood chemistry studies. As the levels of lactate dehydrogenase (LDH) can be higher than normal when you have melanoma, you will be informed to check this enzyme in your blood. But note that LDH levels may not be checked for early stage disease.
- Skin biopsy. It usually refers to removing a sample of tissue for testing, and is the only way to confirm melanoma. The sample removed from your skin is sent to a lab for examination. If at all possible, the entire suspected area should be removed.
- Lymph node biopsy. If melanoma is diagnosed, your doctor may need to find out if cancer cells have spread, though they won't do this for melanoma in situ. The first step is to perform a sentinel node biopsy.
- Imaging tests. Imaging tests are used to see if cancer has spread beyond the skin to other parts of the body. These tests include CT scan, MRI and PET scan.
7. What are the Treatment of Melanoma?
If there's a diagnosis of melanoma, it's important to determine the stage. This will provide information on your overall outlook and help guide treatment. Treatment depends on the stage of melanoma. Melanoma is staged based on the size of the tumor and the extent to which the cancer has spread. The stages of melanoma are divided into five stages. We collect the stages and treatments of melanoma on the following table.
||The tumor is in the epidermis and has not spread elsewhere.
||The suspicious tissue of melanoma in stage 0 is possible to be completely removed during a biopsy. You may not need further treatment.
||The tumor is less than 2 mm thick, is developing slowly and hasn't spread to other organs.
||Very thin melanomas can be completely removed during biopsy. If not, they can be surgically removed later. This involves removing the cancer along with a margin of healthy skin and a layer of tissue underneath the skin. Early-stage melanoma doesn't necessarily require additional treatment.
||The tumor is from 1-4+ mm thick, may be ulcerated, and hasn't spread to other organs.
||The cancer has spread to nearby skin or lymph nodes, lymph nodes may be enlarged, and the developing tumor may be ulcerated.
||In stage 3, wide-excision surgery is used to remove the tumor and affected lymph nodes. In stage 4, The skin tumors and some enlarged lymph nodes can be removed by surgery. Moreover, you also need to have surgery to remove tumors on internal organs based on the number, size, and location of tumors.
||The cancer has spread to distant organs or lymph nodes. At this stage the cancer may be referred to as a metastatic melanoma.
Besides, stages 3 and 4 generally require some additional treatments, involving:
- Immunotherapy drugs. Currently, the immunotherapy drugs usually include interferon or interleukin-2 (IL-2) or checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab.
- Targeted therapy for those cancers related to mutations in the BRAF gene. These may include cobimetinib, dabrafenib, trametinib, and vemurafenib.
- Targeted therapy for melanoma related to mutations in the C-KIT gene. These may include imatinib and nilotinib.
- Vaccines. These may include Bacille Calmette-Guerin (BCG) and T-VEC (Imlygic).
- Radiation therapy. This is used to shrink tumors and to kill cancer cells that may have been missed during surgery. Radiation can also help relieve symptoms of cancer that has metastasized.
- Isolated limb perfusion. This involves infusing only the affected arm or leg with a heated solution of chemotherapy.
- Systemic chemotherapy. This may include dacarbazine (DTIC) and temozolomide (Temodar), which may be used to kill cancer cells throughout your body.
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