Melanoma

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Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye.

Melanoma is the most dangerous type of skin cancer. Although melanoma makes up only 4% of skin cancers,  it causes 77% of skin cancer deaths. About 100,000 cases of melanoma are diagnosed each year.

Surgery to remove melanoma is the standard initial treatment. The tumor and a portion of normal tissue surrounding the tumor, called the margin, must be removed to reduce the chance that any cancer remains. When melanoma is caught early, and can be removed by surgery, chances for successful treatment are much higher.

Worldwide, doctors diagnose approximately 160,000 new cases of melanoma annually. The diagnosis is more frequent in women than in men and is particularly common among Caucasians living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe. Organ transplant recipients have a 3 to 4-fold higher risk for melanoma compared to general population.

Where Melanoma Occurs

Melanoma can occur in any part of the body that contains melanocytes. In men, melanoma is often found on the trunk (the area from the shoulders to the hips) or the head and neck. In women, melanoma often develops on the arms and legs. Melanoma usually occurs in adults, but it is sometimes found in children and adolescents. 

 

Melanoma of the back
This 38 year old patient noticed that a previously flat mole had changed and become larger in diameter and protruded outward from his skin (This fulfills the E for Evolution rule of the ABCDE's).

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melanoma1
Melanoma of the nail bed
Melanoma can occur in unusual areas, including the hands, feet and even the eye


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melanoma2
Melanoma of the posterior calf
This melanoma is asymmetric, has an irregular border, has multiple colors within the lesion (brown, black, tan) and is > 0.6cm in diameter.


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 melanoma3

Text and Images courtesy of UCSF Department of Dermatology

 

Signs and Symptoms

Melanoma typically presents as a brown or black spot with irregularities in symmetry, border and color. Melanoma may develop within an existing mole or on previously normal appearing skin. Melanoma has a high fatality rate because its cells can break off and spread throughout the body (metastasize). 

Most skin melanomas do not have any associated symptoms early in their development, but itching, bleeding, and pain can eventually develop. Melanomas in the eye can cause pain or vision problems (like blurry vision, double vision, or partial or complete loss of vision. Rarely, melanoma is not pigmented and is more difficult to diagnose. It may appear as a non-healing ulcer or a new scar-like lump in the skin.

A doctor should be consulted if any of the following occur:

  • A mole that::
    • changes in size, shape, or color.
    • has irregular edges or borders.
    • is more than 1 color.
    • is asymmetrical (if the mole is divided in half, the 2 halves are different in size or shape).
    • itches.
      oozes, bleeds, or is ulcerated (a hole forms in the skin when the top layer of cells breaks down and the tissue below shows through). 
  • Change in pigmented (colored) skin.
  • Satellite moles (new moles that grow near an existing mole).

The warning signs of melanoma sometimes are referred to as ABCDE. The "ABCDE rule" is an easy guide to the usual signs of melanoma. Be on the look out and promptly notify your primary care physician or dermatologist about any spots that match the following description. Some melanomas do not fit the ABCDE rule described above, so it is important for you to notice changes in skin markings or new spots on your skin.

 

asymmetry (A) Asymmetry - One half doesn't match the other half.
borderirregularity (B) Border Irregularity - The edges are ragged, notched or blurred.
color (C) Color - The pigmentation is not uniform. Shades of tan, brown, and black are present. Dashes of red, white, and blue add to the mottled appearance.
diameter (D) Diameter - The width is greater than six millimeters (about the size of a pencil eraser). Any growth of a mole should be of concern.
  (E) Evolution: the symmetry, border, color, or diameter of a mole has changed over time.

Text and Images courtesy of UCSF Department of Dermatology 

Risk Factors

Unusual moles, exposure to sunlight, and health history can affect the risk of developing melanoma. Ultraviolet radiation, which is present in sunlight and in tanning beds, probably sets off many cases of melanoma by causing genetic damage in melanocytes. Children and adolescents are especially sensitive to the effects of ultraviolet light.

Risk factors for melanoma include:

  • Having a fair complexion, which includes the following:
    • Fair skin that freckles and burns easily, does not tan, or tans poorly.
    • Blue or green or other light-colored eyes.
    • Red or blond hair.
  • Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) over long periods of time.
  • Having a history of many blistering sunburns as a child.
  • Having several large or many small moles.
  • Having a family history of unusual moles (atypical nevus syndrome).
  • Having a family or personal history of melanoma.
  • Being white and male. 
  • Having an organ transplant

Melanoma and Organ Transplant Recipients

Overall, organ transplant recipients have a 3 to 4-fold greater risk of developing melanoma.

  • Melanoma accounts for 6% of post-transplant skin cancers in adult transplant receipients
  • Melanoma accounts for 12-15% of post-transplant skin cancers in pediatric organ transplant recipients
  • Transplant recipients with a pre-transplant history of melanoma have a 20% risk of recurrence

Subtypes of Melanoma

The most common appearance of a skin melanoma is a changing, irregular appearing growth or dark spot. While most melanomas produce pigment and tend to look dark, melanomas known as amelanotic melanoma can also appear with little or no visible pigment. But these still produce melanin at the cellular level that may not be detected by the naked eye. Melanoma has been broken down into several different types based on their clinical appearance as well as how they appear under a microscope (histopathological features):

  • Superficial Spreading Melanoma is most common type of melanoma, in which early on, the growth is flat and outward on the surface of the skin (like spokes on a wheel, known as the radial growth phase). This phase may last for months or even years. Eventually, the melanoma begins to grow inward into the skin, which can have the appearance of a bump above the skin (called the vertical growth phase). Superficial spreading melanomas can be detected using the "ABCDE" abbreviation, where A stands for asymmetry, B border irregularity, C color variation, D diameter enlargement, and E evolution or change in the spot (see below).
  • Nodular melanomas are the next most common type of melanoma, and grow as a lump or bump (with or without noticeable pigment) directly into the skin without an obvious flat phase.
  • Acral Lentiginous Melanomas appear in areas of skin without hair, including the palms, soles, and underneath the nail. Melanomas on the palms and soles usually appear as darker spots, but melanomas in the nail can look like red bumps and be mistaken for a fungus infection.
  • Lentigo maligna melanomas can look like a dark freckle that is growing, and occur as a result of chronic sun exposure. They are usually seen in areas such as the scalp, face, neck, and arms with signs of sun damage.
  • Desmoplastic melanomas are a type of melanoma that is being seen more frequently recently. These melanomas tend to start in the same regions as lentigo maligna melanomas, but they usually do not produce a lot of pigment and can have a deceiving appearance that does not look like an ordinary melanoma. Desmoplastic melanomas usually show up as a reddish or flesh-colored lump or bump and can be mistaken for a cyst or scar.

 

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Diagnosis 

If there is suspicion that  that a spot on the skin is melanoma, it must be biopsied to obtain a definite diagnosis. In this procedure, the goal is remove all of the suspicious-looking growth. If this is not possible due to the tumor's size or other limitations, then a  sample of the tissue is removed. Several biopsy techniques are described below.

Excisional Biopsy

This type of biopsy attempts to remove the growth in its entirety. In general this is the best approach because it allows the pathologist who reviews the tissue to examine the entire growth. Depending on the size and the location of the growth, an excisional biopsy can be performed using a number of different techniques, including:

  1. Elliptical excision, in which the growth is removed by cutting around it with a scalpel and sewing the skin together
  2. Punch biopsy, in which a cylindrical instrument (called a punch) is used to remove the mole and a small area of normal skin around it
  3. Shave biopsy, in which a scalpel alone is used to get underneath the growth. Elliptical and punch biopsies require sutures, whereas shave biopsies do not. However, shave biopsies may not always remove the entire growth, so they should be performed by experienced health care professionals when a melanoma is suspected. 

Incisional Biopsy

This type of biopsy attempts to remove a piece of the growth. This is usually not the preferred approach but sometimes has to be used if the suspected melanoma is unusually large, in a sensitive location (such as the face), or in which complete removal would require drastic surgery.

For incisional biopsies, the same three approaches described for excisional biopsies would typically be used. Once the biopsy is performed, it is sent to a pathology laboratory for review by a pathologist, who makes the final diagnosis. For a suspected eye melanoma, the diagnosis is made on clinical examination of the growth in the eye by an experienced ophthalmologist, and a biopsy is not usually performed. When melanoma appears in unusual locations such as the lymph nodes or internal organs, a partial biopsy of the involved area or complete removal of the growth is performed to make the diagnosis.

Role of Pathologist

A pathologist then examines the tissue under a microscope to check for cancer cells. Often, the pathologist can easily tell whether these cells represent melanoma or a non-cancerous mole. Sometimes, however, the distinction can be tricky, and special stains or further diagnostic tests must be performed to make the diagnosis. Distinguishing between cancerous and non-cancerous tumors can make all the difference for a patient, as the treatment and outcomes can be very different.

A pathologist can identify many other characteristics of the melanoma to determine how likely the cancer can be successfully treated. If a biopsy was performed at another medical center, an experienced pathologist at UCSF to review those results.

Staging Tests for Melanoma 

After melanoma has been diagnosed, tests are done to find out if cancer cells have spread within the skin or to other parts of the body. The process used to find out whether cancer has spread within the skin or to other parts of the body is called staging. It is important to know the stage in order to plan treatment. 

Staging Tests

The following tests and procedures may be used in staging: 

  • Wide local excision: A surgical procedure to remove some of the normal tissue surrounding the area where melanoma was found, to check for cancer cells.
  • Lymph node mapping and sentinel lymph node biopsy: Procedures in which a radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through lymph ducts to the sentinel node or nodes (the first lymph node or nodes where cancer cells are likely to have spread). The surgeon removes only the nodes with the radioactive substance or dye. A pathologist then checks the sentinel lymph nodes for cancer cells. If no cancer cells are detected, it may not be necessary to remove additional nodes.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. For melanoma, pictures may be taken of the chest, abdomen, and pelvis.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Laboratory tests: Medical procedures that test samples of tissue, blood, urine, or other substances in the body. These tests help to diagnose disease, plan and check treatment, or monitor the disease over time.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. For melanoma, the blood is checked for an enzyme called lactate dehydrogenase (LDH). 

Staging System for Melanoma

Stage 0

These melanomas are confined to the top most layer of the skin, called the epidermis. In most cases, patients can be cured with surgery to remove the cancer. However, these patients should be monitored for the small risk of melanoma recurrence as well as the development of a second, unrelated skin melanoma.

Stage I

 Unlike stage 0 melanoma, these melanomas have invaded through the epidermis. They are considered to be the thinnest of the "invasive" melanomas. There is a small chance that some of these melanomas have spread microscopically to the lymph nodes. In cases with a substantial risk of lymph node involvement, a sentinel lymph node biopsy may be performed, usually at the same time as the surgical removal of the skin melanoma.

Stage II

These are thicker melanomas that have invaded deeper into the skin. As a melanoma becomes deeper, there is a greater possibility that it can spread to other sites in the body. Sentinel lymph node biopsies may be performed when the skin melanoma is surgically removed. In cases where there is a high risk of melanoma developing elsewhere in the body, adjuvant treatment - treatment that attempts to lower the risk of melanoma recurrence - may be offered after the surgery.

Stage III

These include melanomas that have spread to the local lymph nodes. These melanomas have a substantial risk of recurring, or manifesting in distant organs. Therefore adjuvant therapy - treatment that attempts to lower the risk of melanoma recurrence - is offered after the melanoma is surgically removed. Radiation treatment may be considered in certain patients.

Stage IV

In this stage, the cancer has spread to distant organs. In general, patients are treated with systemic therapy, or therapy that targets the entire body. Radiation treatment may be recommended, as well as experimental treatments as part of a clinical trial or study.

Treatment

Melanoma Surgery

Treatment includes surgical removal of the tumor, adjuvant therapy, chemotherapy, immunotherapy, radiation and experimental therapies, including a new generation of targeted agents being investigated in clinical trials. The chance of a cure is greatest when the tumor is discovered while still small and, thin, and where the entire tumor can be removed surgically.

Surgery to remove melanoma is the standard initial treatment. It is necessary to remove not only the tumor but also some normal tissue around it, called the margin, to reduce the chance that any cancer remains. The width and depth of surrounding skin to be removed depends on the thickness of the melanoma and how deeply it has invaded the skin.

When the melanoma is very thin, the biopsy may remove all the cancerous tissue and no additional surgery may be necessary. For thick melanomas, it may be necessary to take out a larger margin of tissue. Deeper melanomas have a higher chance of spreading to the lymph nodes. For these cases, a sentinel lymph node biopsy may be performed to determine if the cancer has spread.

Surgery alone may not effectively control melanoma that has spread to other parts of the body. Other treatment may be required such as chemotherapy, biological therapy or immunotherapy, radiation therapy or a combination of these methods.

Following the initial biopsy, every melanoma undergoes a further surgery (called re-excision or wide excision) to remove the skin around the original site of the tumor in order to ensure complete removal and to reduce the risk of regrowth (recurrence) of the tumor at that site.

The amount of skin to be removed (called the re-excision margin) depends on the thickness of the melanoma, with increasing margins for increasing categories of thickness, from five millimeters on either side of the scar for melanoma in situ to potentially two centimeters on either side for melanoma over four millimeters thick.

However, it is important to note that the surgical approach to every melanoma should be customized based on the specific details of the patient and the melanoma, location of the melanoma, and how the resultant wound would be repaired. A simple excision of a melanoma can usually be accomplished by sewing the skin together, resulting in a linear scar. Wider margins of excision can require more complex ways of closing the wound, including skin grafts (in which skin is taken from another area of the body to cover the wound) or flaps (in which nearby tissue is moved over to cover the wound). In most instances, wide excision alone can be performed under local anesthesia in the physician's office.

Sentinel Lymph Node Biopsy (SLNB)

The other important use of surgery for melanoma is removal of the regional lymph nodes to identify whether melanoma has spread. Initially, the physician evaluating the patient with a skin melanoma will feel the lymph nodes to determine whether there are any enlarged lymph nodes, which can undergo biopsy directly.

In most patients with primary melanoma, no lymph nodes can be felt, so the question is whether melanoma has spread to lymph nodes microscopically. To date, only lymph node surgery can determine whether this has occurred. Historically, this was accomplished by complete removal of all of the lymph nodes of the suspected region, called elective lymph node dissection (ELND), which could require radical surgery. 

Recently, a technique called sentinel lymph node biopsy (SLNB) has largely replaced ELND to evaluate the regional lymph nodes. The sentinel node(s) is considered to be the first lymph node that the cancer cells encounter as they travel along the lymphatic vessels. In this technique, usually a blue dye and a radioactive tracer are injected at the site of the tumor (or where the tumor used to be before its removal by biopsy) at the time of the re-excision.

After injecting the dye and tracer, a nuclear medicine scan is performed to identify the sentinel lymph node, which shows uptake of the tracer on the scan. If the sentinel node has tumor cells in it ("positive" lymph node"), the current practice is to remove other lymph nodes in the area. In general, lymph node surgery requires general anesthesia, although the SLNB procedure can be performed without staying in the hospital

Benefits of SLN Biopsy

Recent studies have shown that patients with an involved (or "positive") sentinel lymph node have a higher risk of recurrence than those who have a negative sentinel node. For melanoma patients, SLN biopsy is  low-risk procedure that helps to identify high-risk patients who might benefit from more aggressive therapy, such as selective or complete lymphadenectomy or adjuvant treatment (after surgery) with interferon alfa-2b. This may lower lower the risk of melanoma recurrence,

Another major benefit of the procedure is preventing extensive surgery on regional lymph nodes when the sentinel node is negative. Whether removing the lymph nodes prolongs survival of patients with melanoma is still being studied.

When melanoma has spread beyond the regional lymph nodes, surgery can still be important in specific situations either to establish the diagnosis, remove all evidence of the tumor, or control symptoms produced by the tumor.

Other Standard Treatment

Chemotherapy

Chemotherapy is the use of drugs to kill cancer cells. It is generally a systemic therapy, meaning that it can affect cancer cells throughout the body. In chemotherapy, one or more anticancer drugs are given orally or by injection into a blood vessel.

Chemotherapy usually is given in cycles - a treatment period followed by a recovery period, then another treatment period, and so on. Chemotherapy can be administered in a clinic, doctor's office, hospital or at home. Depending on the drugs given and your general health, a short hospital stay may be needed.

Biological Therapy

Biological therapy, also called immunotherapy, is a form of treatment that uses the body's immune system, either directly or indirectly, to fight cancer or to lessen side effects caused by some cancer treatments. Biological therapy also is a systemic therapy and involves the use of substances called biological response modifiers (BRMs). The body normally produces these substances in small amounts in response to infection and disease. Using modern laboratory techniques, scientists can produce BRMs in large amounts for use in cancer treatment.

In some cases, biological therapy given after surgery can help prevent melanoma from recurring. For patients with metastatic melanoma or a high risk of recurrence, interferon-alfa and interleukin-2 may be recommended after surgery. Colony-stimulating factors and tumor vaccines are examples of other BRMs under study.

Radiation Therapy

In some cases, radiation therapy, also called radiotherapy, is used to relieve some of the symptoms caused by melanoma. Radiation therapy is the use of high-energy rays to kill cancer cells. Radiation therapy is a local therapy that affects cells only in the treated area. Radiation therapy is most commonly used to help control melanoma that has spread to the brain or bones, and other parts of the body.

Experimental Therapies

Trials under investigation for treatment of melanoma include:

  • Chemoimmunotherapy is the use of anticancer drugs combined with biologic therapy to boost the immune system to kill cancer cells.
  • Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is a type of targeted therapy being studied in the treatment of melanoma.
    • Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Monoclonal antibodies may be used in combination with chemotherapy as adjuvant therapy.
  • Vaccine therapy is a type of biologic therapy. Cancer vaccines work by helping the immune system recognize and attack specific types of cancer cells. Vaccine therapy can also be a type of targeted therapy.

UCSF has numerous clinical trials underway testing some of these treatments.

Genetic Mutations in Melanoma

All melanomas are not alike. Scientists have discovered that melanomas tend to have specific mutations in their DNA, depending on where they originated.

The UCSF Melanoma Center has the ability to analyze cancer cells to test for specific mutations, including the genes known as BRAF, NRAS and KIT. A mutation in one of the genes may cause the melanoma to be more responsive to certain treatments. We offer mutation testing to patients who are identified as most likely to benefit from this service.

Credits: Portions of the text on this page were reproduced, modified or adapted from either works in the public domain, freely licensed media file repositories, or from other UCSF websites. Here the sources used were: the websites of the National Cancer Institute (NCI) - Melanoma (cancer.gov), the originator of the content; Mohammed. Skin Cancer: Melanoma [Internet]. Version 6. Knol. 2008 Jul 21 under a Creative Commons Attribution 3.0 License; UCSF Medical Center and UCSF Department of Dermatology web pages focused on melanoma.

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