About the skin
The skin is the largest organ in the body. It protects against infections and injuries and helps regulate body temperature. The skin also stores water and fat and produces vitamin D.
The skin consists of 3 main layers:
Epidermis: the outer layer of the skin
Dermis: the inner layer of the skin
Subcutaneous: the deep layer of fat
The deeper layer of the epidermis, located just above the dermis, contains cells called melanocytes. Melanocytes produce skin color. Melanoma begins when healthy melanocytes change and go out of control, forming a cancerous tumor. A cancerous tumor is malignant, which means it can grow and spread to other parts of the body (metastasis). Sometimes, melanoma develops on a wart (“mole”) that a person already has on their skin. When this happens, the mole will undergo changes that are usually observed, such as changes in its shape, size, color or boundaries (see also Symptoms).
Melanoma can develop anywhere on the body, including the head and neck, the skin under the nails, the genitals, and even the soles of the feet or the palms of the hands. The melanoma may not be colored like a wart (mole). It may be colorless or slightly red, which is called non-ameliorative melanoma.
If it is detected early, melanoma can often be treated with surgery. However, melanoma is one of the most serious forms of skin cancer. It can develop deep inside the skin, called invasive melanoma. It can also invade the lymph nodes and blood vessels and spread to distant parts of the body, called metastatic melanoma.
Skin melanoma is the melanoma that first develops on the skin. Melanoma can also develop in the mucous membranes lining the mouth, gastrointestinal tract, a woman’s vagina, etc. Melanoma may also develop in the eye.
Changes in the size, shape, color, or feel of a wart (mole) are often the first warning signs of melanoma. These changes can occur in an existing wart, or melanoma can appear as a new or unusual type of wart. The “ABCDE” rule is useful for remembering the warning signs of melanoma:
Asymmetry. The shape of half of the wart does not match the other half of the wart.
Border. The boundaries are vague, uneven, or blurred.
Color. There may be shades of black, brown, and dark, deep tan. Areas of white, gray, red, or blue may also be observed.
Diameter. The diameter is usually greater than 6 mm or has increased in size in a relatively short time.
Evolving. The mole (wart) changes in size, shape, color, or appearance or grows in an area of normal skin. Also, when melanoma develops in an existing olive, the texture of the olive can change and become hard or amorphous. Although skin damage may appear different and may cause itching, hot flashes, or bleeding, melanoma usually does not cause pain.
When to see a doctor
Many melanomas are dark brown or black and are often described as changed, different, unusual, or “ugly in appearance”. However, any skin abnormality that develops or changes rapidly and does not disappear, colored or not, should be examined by a doctor (dermatologist). Bleeding may be a sign of advanced melanoma. In addition, the appearance of a new and unusual look of the mole is more likely to be melanoma.
If you are worried about a new mole or an existing mole, talk to your dermatologist.
For melanoma, a biopsy of the suspected skin area is the only sure way for the doctor to know if it is cancer. In a biopsy, the doctor takes a small sample of tissue that he sends for histological examination to a pathological laboratory. Your doctor may suggest other tests that will help him diagnose and determine the overall stage of melanoma.
This section describes melanoma diagnosis options. Not all of the following tests will be used for each person. Your doctor will look at several factors, described below while choosing diagnostic tests for each person.
Biopsy and histological examination of skin lesions
Only a biopsy can make a definite diagnosis. The doctor will remove part or of the suspected skin lesion, usually ensuring that the entire lesion is preserved so that the pathologist can carefully examine the thickness of possible cancer and its scope (healthy tissue around the lesion).
The pathologist is the physician who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose diseases (histological examination).
The pathologist will write a report, called a histological examination, which will include the following information:
The thickness of the melanoma
Presence or absence of ulceration
If the cells can be divide, which is called the mitotic index, the report will include the type/subtype of the melanoma.
Presence of immune cells called lymphocytes that penetrate the tumor
Marginal condition, which describes whether melanoma cells can be seen in the deep and / or peripheral (lateral) edges of the biopsy sample
Types of skin melanoma described by the pathologist:
The 4 most common types of skin melanoma are:
Superficially expanding melanoma. This is the most common type, accounting for 70% of melanoma. It usually grows on an existing wart (mole).
Lentiginous melanoma. This type of melanoma tends to occur in the elderly. It often begins on the face, ears, and hands and on the skin that is often exposed to the sun.
Nodular melanoma. This type accounts for about 15% of melanoma. It often appears quickly, is usually black, but maybe pink or red.
Acral Lentiginous melanoma of the extremities. This type of melanoma develops on the palms of the hands, the soles of the feet, or under the nails. Phacoid melanoma of the extremities is not related to sun exposure.
Thickness of the melanoma
The thickness of the primary melanoma is the most reliable feature that helps doctors predict the risk of cancer spreading. To do this, the pathologist will measure the depth of the melanoma from the top of the skin to the bottom stage of the melanoma in the underlying skin.
Thin. A melanoma tumor less than 1 mm thick is characterized as “thin.” A thin melanoma is associated with a low risk of spreading to the peripheral lymph nodes or to distant parts of the body.
Intermediate. An intermediate thickness melanoma is between 1 mm and 4 mm.
Thick. A thick melanoma, more than 4 mm thick, is more likely to recur after treatment, called relapse. This is because cancer has sometimes spread to other parts of the body by the time it is diagnosed.
The presence or absence of ulceration of the primary melanoma is defined in the histological examination report. Ulceration is the loss of skin surface. If the melanoma is ulcerated, research has shown that the risk of spread (metastasis) and recurrence (recurrence after removal) increases significantly.
Another feature of melanoma, defined by the pathologist on histological examination, is the mitotic index, which refers to the assessment of the percentage rate of growth, of the proliferation of cancer cells. The pathologist measures the number of mitoses per square millimeter (mm2).
In combination with the thickness and presence of ulceration, the rhythm of mitotic activity can be used to determine the stage, treatment options, and prognosis.
Targeted treatment & molecular types of melanoma
Melanoma is usually classified according to histological types (see Diagnosis), which are based on how the cells appear under the microscope and are reflected in the report made by the pathologist on histological examination. Recent information has shown that melanoma can also be classified into molecular (genetic) subtypes. These molecular subtypes are based on the separate genetic changes of melanoma cells, called mutations. These mutations include:
The most common mutation in melanoma is in the BRAF gene, which mutates in about 50% of skin melanomas.
The NRAS mutates in approximately 20% of people with melanoma.
NF-1 mutations occur in about 10% to 15% of people with melanoma.
These mutations are more common in melanoma that develops in the mucous membranes of the body’s organs, in melanoma of the hands or feet, or in melanoma of the skin that occurs after chronic exposure to the sun.
Some melanomas do not have mutations in BRAF, NRAS, NF-1 or KIT genes. These tumors have other genetic changes that force them to grow. Researchers are trying to target other mutations in these tumors in clinical trials.
The classification of melanoma into different molecular subtypes based on genetic mutations may have a major effect on the types of treatment used on advanced melanoma. Targeting specific mutated genes is an important new way to treat invasive melanoma, called targeted therapy.
Researchers are studying new checkpoint inhibitors and immunotherapies that are directed to other parts of the immune system. These include TIM3, LAG3, and IDO inhibitors. Various combinations of immunotherapies are also considered, including all of the above factors with anti-PD-1 or anti-PD-L1 antibodies, as well as combinations of targeted immunotherapy treatments.
Consult your oncologist
Sentinel lymph node & Lymphatic mapping
Lymph nodes are tiny bean-shaped organs that help fight infections. Melanoma can develop deep in the inner layers of the skin and spread to the lymph nodes and other parts of the body.
The sentinel lymph node biopsy – also called SLNB (Sentinel Lymph Node Biopsy), is a surgical procedure that helps the doctor understand if cancer has spread to lymph nodes. When cancer spreads to the area where it started in the lymph nodes, it travels through the lymphatic system. A lymph node guard is the first lymph node in which the lymphatic system is channeled. Because melanoma can start anywhere on the skin, the position of the sentinel lymph node will be different in each patient, depending on the position of the body where cancer started.
To find the lymph node sentinel, a dye and a harmless radioactive substance are injected as closely as possible where the melanoma started. The substance tracer then reaches the sentinel lymph node, making it visible. The doctor then removes 1 or more of these lymph nodes to check if the pathologist has melanoma cells, leaving behind most of the other lymph nodes in that area. The pathologist analyzes the lymph nodes, examines them under a microscope, and then provides a report called a histological examination.
If no melanoma cells are found in the sentinel lymph node, further surgical removal of the lymph nodes is not required. If the sentinel lymph node contains melanoma, this is called a positive lymph node guard and this means that the disease has spread and it may be recommended to remove more lymph nodes, called lymph node dissection.
Lymph node guard biopsy is usually recommended for people with melanoma greater than 1.0 mm thick or ulcerated (see Diagnosis).
Your doctor will discuss whether this approach is recommended based on this and other features of the primary melanoma and combined with other factors.
Frequently Asked Questions (FAQ)
Finding a mutation in the BRAF gene is an indication for targeted therapy (BRAF inhibitors).
Similarly, if no mutation is found in the BRAF gene, finding a mutation in the KIT gene is an indication for targeted therapy (KIT inhibitors).
Finding a mutation in the NRAS gene is an indication for targeted therapy (MEK inhibitors)
Finding mutations in genes NTRK1, NTRK2, NTRK3, ALK, ROS1 is an indication for targeted therapy response with the corresponding inhibitors (eg TRK inhibitors).
The test is performed on the biopsy material or surgical specimen (paraffin block) on which your histological examination was conducted.
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