Melanoma Research Paper

Research into the causes, prevention, and treatment of melanoma is being done in medical centers throughout the world.

Causes, prevention, and early detection

Sunlight and ultraviolet (UV) radiation

Recent studies suggest there may be 2 main ways that UV exposure is linked to melanoma, but there is likely some overlap.

The first link is to sun exposure as a child and teenager. People with melanoma often have an early history of sunburns or other intense sun exposures, although not everyone does. This early sun exposure may damage the DNA in skin cells (melanocytes), which starts them on a path to becoming melanoma cells many years later. Some doctors think this might help explain why melanomas often occur on the thighs (in women) and trunk (in men), areas that generally aren’t exposed to the sun as much in adulthood.

The second link is to melanomas that occur on the arms, neck, and face. These areas are chronically exposed to sun, particularly in men.

Tanning booths might help either kind of melanoma to develop.

Researchers are studying if melanomas that develop from these types of UV exposure have different gene changes that might require them to be treated differently.

Public education

Most skin cancers can be prevented. The best way to lower the number of skin cancers and the pain and loss of life from this disease is to educate the public, especially parents, about skin cancer risk factors and warning signs. It’s important for health care professionals and skin cancer survivors to remind everyone about the dangers of too much UV exposure (both from the sun and from man-made sources such as tanning beds) and about how easy it can be to protect your skin from UV rays.

Melanoma can often be found early, when it is most likely to be cured. Monthly skin self-exams and awareness of the warning signs of melanomas may be helpful in finding most melanomas when they are at an early, curable stage.

The American Academy of Dermatology (AAD) sponsors annual free skin cancer screenings throughout the country. Many local American Cancer Society offices work closely with the AAD to provide volunteers for registration, coordination, and education efforts related to these free screenings. Look for information in your area about these screenings or call the American Academy of Dermatology for more information.

Along with recommending staying in the shade, the American Cancer Society uses a slogan popularized in Australia as part of its skin cancer prevention message in the United States. “Slip! Slop! Slap!®… and Wrap” is a catchy way to remember when going outdoors to slip on a shirt, slop on sunscreen, slap on a hat, and wrap on sunglasses to protect your eyes and the sensitive skin around them.

Melanoma genetic research

Scientists have made a great deal of progress in understanding how UV light damages DNA inside skin cells and how these changes can cause normal skin cells to become cancer cells.

Some people, though, inherit mutated (damaged) genes from their parents. For example, changes in the CDKN2A (p16) gene cause some melanomas that run in certain families. People who have a strong family history of melanoma should speak with a cancer genetic counselor or a doctor experienced in cancer genetics to discuss the possible benefits, limits, and downsides of testing for changes in this gene.

Diagnosis

Some newer approaches to diagnosing skin cancer don’t require the removal of a skin sample. An example of such an “optical biopsy” is reflectance confocal microscopy(RCM). This technique allows the doctor to look at an abnormal area of skin to a certain depth without cutting into the skin.

RCM is used widely in Europe, and it’s now available in some centers in the US. It may be especially useful for people with many unusual moles, as it can cut down on the number of skin biopsies these people need. RCM might also be helpful in determining the edges of a melanoma, which could help during surgery.

This technique will likely become more widely available in the coming years.

Lab tests to help determine prognosis

Most melanomas found at an early stage can be cured with surgery. But a small portion of these cancers eventually spread to other parts of the body, where they can be hard to treat.

Recent research has shown that certain gene expression patterns in melanoma cells can help show if stage I or II melanomas are likely to spread. A lab test based on this research, known as DecisionDx-Melanoma, is now available. The test divides melanomas into 2 groups based on their gene patterns:

  • Class 1 tumors have a low risk of spreading.
  • Class 2 tumors have a higher risk of spreading.

This test might help tell if someone with early-stage melanoma should get additional treatment or if they need to be followed more closely after treatment to look for signs of recurrence.

Treatment

While early-stage melanomas can often be cured with surgery, more advanced melanomas can be much harder to treat. But in recent years, newer types of immunotherapy and targeted therapies have shown a great deal of promise and have changed the treatment of this disease.

Immunotherapy

This type of treatment helps the body’s immune system attack melanoma cells more effectively. Some forms of immune therapy are already used to treat some melanomas (see Immunotherapy for Melanoma Skin Cancer).

Immune checkpoint inhibitors: Newer drugs such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) block proteins that normally suppress the T-cell immune response against melanoma cells. These drugs have been shown to help some people with advanced melanomas live longer.

Researchers are now looking for ways to make these drugs work even better. One way to do this might be by combining them with other treatments, such as other types of immunotherapy or targeted drugs.

Researchers are also studying if these drugs can be helpful for earlier-stage melanomas. For example, some might be useful before or after surgery for some melanomas to help lower the chance that the cancer will come back.

Newer immune checkpoint inhibitors with slightly different targets are now being studied as well.

Melanoma vaccines: Vaccines to treat melanoma are being studied in clinical trials.

These vaccines are, in some ways, like the vaccines used to prevent diseases such as polio, measles, and mumps that are caused by viruses. Such vaccines usually contain weakened viruses or parts of a virus that can’t cause the disease. The vaccine stimulates the body’s immune system to destroy the more harmful type of virus.

In the same way, killed melanoma cells or parts of cells (antigens) can be used as a vaccine to try to stimulate the body’s immune system to destroy other melanoma cells in the body. Usually, the cells or antigens are mixed with other substances that help boost the immune system as a whole. But unlike vaccines that are meant to prevent infections, these vaccines are meant to treat an existing disease.

Making an effective vaccine against melanoma has proven to be harder than making a vaccine to fight a virus. The results of studies using vaccines to treat melanoma have been mixed so far, but many newer vaccines are now being studied and may hold more promise.

Other immunotherapies: Other forms of immunotherapy are also being studied. Some early studies have shown that treating patients with high doses of chemotherapy and radiation therapy and then giving them tumor-infiltrating lymphocytes (TILs), which are immune system cells taken from tumors, can shrink melanoma tumors and possibly prolong life as well. Newer studies are looking at changing certain genes in the TILs before they are given to see if this can make them more effective at fighting the cancer. This approach has looked promising in early studies, but it’s complex and is only being tested in a few centers.

Many studies are now looking to combine different types of immunotherapy, which may be more effective than any single treatment for advanced melanoma.

Targeted drugs

Targeted therapy drugs target parts of melanoma cells that make them different from normal cells. These drugs work differently from standard chemotherapy drugs. They may work in some cases when chemotherapy doesn’t. They may also have less severe side effects.

Drugs that target cells with BRAF gene changes: About half of all melanomas have changes in the BRAF gene, which helps the cells grow. Drugs that target the BRAF protein, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), as well as drugs that target the related MEK proteins, such as trametinib (Mekinist) and cobimetinib (Cotellic), have been shown to shrink many of these tumors. These drugs are now often used to treat advanced melanomas that test positive for the BRAF gene change. Researchers are now looking at whether these drugs might be helpful before or after surgery for some earlier stage melanomas.

Other, similar drugs are now being studied as well.

One of the drawbacks of these drugs is that usually work for only a limited time before the cancer starts growing again. But studies have shown that combining a BRAF inhibitor with a MEK inhibitor results in longer response times, and some side effects (such as the development of other skin cancers) might actually be less common with the combination.

Drugs that target cells with changes in the C-KIT gene: A small number of melanomas have changes in the C-KIT gene. This is more likely in melanomas that start on the palms of the hands, soles of the feet, under the nails, or in certain other places.

Clinical trials are now testing drugs such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna), which are known to target cells with changes in C-KIT.

Drugs that target other gene or protein changes: Several drugs that target other abnormal genes or proteins are now being studied in clinical trials as well. Some examples include axitinib (Inlyta), pazopanib (Votrient), and everolimus (Afinitor).

Researchers are also looking at combining some of these targeted drugs with other types of treatments, such as chemotherapy or immunotherapy.

Melanoma is not the most common type of skin cancer, but it is the most serious because it often spreads. Risk factors for melanoma include overexposure to the sun.

This article explains the symptoms of melanoma, how it is diagnosed, and how it is treated. We also explain how best to prevent melanoma.

Fast facts on melanoma
  • The incidence of melanoma appears to be increasing for people under the age of 40 years, especially women.
  • Avoiding sunburn is an effective way to reduce the risk of skin cancer.
  • Self-monitoring of moles and other markings on the skin can help with early detection.

What is melanoma?


The most common cause of melanoma is excessive sun exposure.

Melanoma is a form of skin cancer that arises when pigment-producing cells—known as melanocytes—mutate and become cancerous.

Most pigment cells are found in the skin, but melanoma can also occur in the eyes (ocular melanoma) and other parts of the body, including, rarely, the intestines. It is rare in people with darker skin.

Melanoma is just one type of skin cancer. It is less common than basal cell and squamous cell skin cancers, but it can be dangerous because it is more likely to spread, or metastasize.

Melanomas can develop anywhere on the skin, but certain areas are more prone than others. In men, it is most likely to affect the chest and the back. In women, the legs are the most common site. Other common sites are the neck and face.

According to the National Cancer Institute, about 87,110 new melanomas were expected to be diagnosed in 2017, and about 9,730 people were expected to die of melanoma.

Stages

The stage at which a cancer is diagnosed will indicate how far it has already spread and what kind of treatment is suitable.

One method of staging melanoma describes the cancer in five stages, from 0 to 4.

Stage 0: The cancer is only in the outermost layer of skin and is known as melanoma in situ.

Stage 1: The cancer is up to 2 millimeters (mm) thick. It has not spread to lymph nodes or other sites, and it may or may not be ulcerated.

Stage 2: The cancer is at least 1.01 mm thick and it may be thicker than 4 mm. It may or may not be ulcerated, and it has not yet spread to lymph nodes or other sites.

Stage 3: The cancer has spread to one or more lymph nodes or nearby lymphatic channels, but not to distant sites. The original cancer may no longer be visible. If it is visible, it may be thicker than 4 mm, and it may also be ulcerated.

Stage 4: The cancer has spread to distant lymph nodes or organs, such as the brain, lungs, or liver.

Types

There are four types of melanoma.

Superficial spreading melanoma: This is the most common, and it often appears on the trunk or limbs. The cells tend to grow slowly at first, before spreading across the surface of the skin.

Nodular melanoma: It is the second most common type, appearing on the trunk, head, or neck. It tends to grow more quickly than other types, turning red—rather than black—as it grows.

Lentigo maligna melanoma: This is less common, and tends to affect older people, especially in parts of the body that have been exposed to the sun over several years. It starts as a Hutchinson's freckle, or lentigo maligna, which looks like a stain on the skin. It usually grows slowly and it less dangerous than other types.

Acral lentiginous melanoma: This is the rarest kind of melanoma. It usually appears on the palms of the hands, soles of the feet, or under the nails. It is more likely in people with darker skin and does not appear to be linked to sun exposure.

Causes

As with all cancers, research is ongoing into the causes of melanoma.

People with certain types of skin are more prone to developing melanoma, and the following factors are associated with an increased incidence of skin cancer:

  • high freckle density or tendency to develop freckles after sun exposure
  • high number of moles
  • five or more atypical moles
  • presence of actinic lentigines, small gray-brown spots, also known as liver spots, sun spots, or age spots
  • giant congenital melanocytic nevus, brown skin marks that present at birth, also called birth marks
  • pale skin that does not tan easily and burns, plus light-colored eyes
  • red or light-colored hair
  • high sun exposure, particularly if it produces blistering sunburn, and especially if sun exposure is intermittent rather than regular
  • age, as risk increases with age
  • family or personal history of melanoma
  • having an organ transplant

Of these, only high sun exposure and sunburn are avoidable.

The World Health Organization (WHO) estimates that around 60,000 early deaths occur each year worldwide because of excessive exposure to the sun's ultraviolet (UV) radiation. An estimated 48,000 of these deaths are from malignant melanoma.

Avoiding overexposure to the sun and preventing sunburn can significantly lower the risk of skin cancer. Tanning beds are also a source of damaging UV rays.

Pictures

If you can tell the difference between a normal mole or freckle and skin cancer, it may help get an early diagnosis.

Symptoms

As with other forms of cancer, the early stages of melanoma may be hard to detect, so it is important to check the skin actively for signs of change.

Alterations in the appearance of the skin are key indicators of melanoma and are used in the diagnostic process.

The Melanoma Research Foundation has produced a web page that compares pictures of melanoma with those of normal moles.

This American non-profit organization also lists the symptoms and signs that should prompt a visit to the doctor.

These are:

  • skin changes, such as a new spot or mole or a change in color, shape, or size of a current spot or mole
  • a skin sore that fails to heal
  • a spot or sore that becomes painful, itchy, or tender, or which bleeds
  • a spot or lump that looks shiny, waxy, smooth, or pale.
  • a firm red lump that bleeds or appears ulcerated or crusty
  • a flat, red spot that is rough, dry, or scaly

ABCDE examination

The ABCDE examination of skin moles is also a key way to reveal suspect lesions. It describes five simple characteristics to look out for in melanoma appearance:

Asymmetric: normal moles are often round and symmetrical, whereas one side of a cancerous mole is likely to look different from the other side - not round or symmetrical.

Border: this is likely to be irregular rather than smooth - ragged, notched, or blurred.

Color: melanomas tend not to be of one color but to contain uneven shades and colors, including varying black, brown, and tan, and even white or blue pigmentation.

Diameter: a change in the size of the mole, or a mole that is larger than a normal mole (more than a quarter inch in diameter) can indicate skin cancer.

Evolving: a change in a mole's appearance over a period of weeks or months can be a sign of skin cancer.

Treatment

The treatment of skin cancer is similar to that of other cancers, but, unlike many internal cancers, it is easier to access the cancer to remove it completely. Surgery is the most common treatment for melanoma.

Surgery involves removing the lesion and some of the normal tissue around it. A biopsy may be taken at the same time.

If melanoma covers a large area of skin, a skin graft may be necessary. If the cancer may have penetrated into the lymph nodes, a lymph node biopsy may be performed.

Other, less common treatments for skin cancer include:

  • chemotherapy
  • biological therapy, using drugs that work with the immune system

Rarely, photodynamic therapy, which uses a combination of light and drugs, and radiation are used.

Prevention


Avoiding excessive exposure to UV radiation reduces the risk of melanoma.

Avoiding excessive exposure to ultraviolet radiation can reduce the risk of skin cancer.

This can be achieved by:

  • avoiding sunburn
  • wearing clothes that protect against the sun
  • using sunscreen with a minimum sun protection factor (SPF) of 15, but preferably SPF 20-30, with 4- or 5-star UVA protection
  • liberally applying sunscreen about half an hour before going out, and applying it again after half an hour
  • reapplying every 2 hours and after swimming to maintain adequate protection
  • avoiding the highest sun intensity between 11 am and 3 pm by finding shade.
  • protecting children by keeping them in the shade, with clothing, and by applying SPF 50+ sunscreen
  • keeping infants out of direct sunlight

Wearing sunscreen is not a reason to spend longer in the sun. Sun exposure should still be limited, where possible. People who work outdoors should take precautions to minimize exposure.

Doctors recommend avoiding tanning booths, lamps, and sunbeds.

What about vitamin D?

Despite warnings against overexposure to the sun, it remains important to get a little sun exposure as this enables our bodies to produce vitamin D.

Vitamin D is an important nutrient for the prevention of diseases such as rickets and osteomalacia. As such, sensible sun exposure is advised.

The time it takes to produce sufficient vitamin D is less than the time it takes to get sunburnt. This means we can enjoy the sun safely and maintain optimal vitamin D levels without dramatically increasing the risk of skin cancer.

Diagnosis

Most cases of melanoma affect the skin. They usually produce changes in existing moles. A person to detect the early signs of melanoma themselves by regularly examining moles and other colored blemishes and freckles.

Any changes in the appearance of the skin should prompt further examination by a doctor. The back should also be checked regularly, especially as 1 in 3 melanomas in men occur on the back. A partner, family member, friend, or doctor can help check the back and other hard-to-see areas.

Cancer doctors are most concerned with lesions that "stand out from the crowd." The ABCDE checklist described above can help with this.

Clinical tests

Doctors may use microscopic or photographic tools to see a lesion in more detail.

If a doctor suspects skin cancer, the patient will be referred to a cancer specialist and a biopsy will be arranged to test the lesion. A biopsy is a procedure where a sample of the lesion is taken for examination in the laboratory.

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