MELANOMA

Melanoma is a form of cancer that arises from melanocytes. Melanocytes are the cells that produce the pigment melanin. It can appear as a mole (melanoma of the skin), but it can also appear in other pigmented tissues (tissues that contain pigment), such as the eye or the intestine.

It is considered the most aggressive form of skin cancer, as it can spread (metastasize) to other parts of the body and cause serious disability or death.

Worldwide, melanoma cases occur most frequently in Australia and New Zealand, where they are 3 times more common than in Europe. On the other hand, melanoma is very rare in African and Asian countries.

In Europe, about 1 in 100 people will develop melanoma at some point in their lives,

But there are significant variations from one country to another. Every year, about 15 per 100,000 people are diagnosed with melanoma. This number is increasing in almost all European countries. Melanoma is slightly more common in women than in men. Melanoma is most common in Switzerland, the Netherlands and the Scandinavian countries and is less common in Mediterranean countries.

The main types of melanoma are:

Superficially Expanding Melanoma: This type accounts for about 70% of all melanoma cases.
Nodular Melanoma: About 20% of melanomas begin as blue-black to purple nodules. They grow quickly and are likely to spread before diagnosis.
Malignant lentigines: Unlike other forms of melanoma, it tends to appear on parts of the body, such as the face, that are exposed to the sun continuously, rather than intermittently. Malignant lentigines look like large, irregularly shaped or colored freckles and grow slowly.
There are also other rarer forms of melanoma, for example, under the nails (subungual melanoma), on the palms and soles, choroidal melanoma (ocular melanoma), on the mucous membrane of the mouth or vagina, or sometimes even in the intestine.

The main risk factors for melanoma are:
Skin type: people with fair skin are at a higher risk of developing melanoma than people with dark skin. The greatest risk is for people with red hair and freckles. Melanoma is very rare in Black or Asian people. When it does occur, it is usually a special type of melanoma called lenticular melanoma that appears on the soles of the feet, palms of the hands, or under the nails.
Moles: A mole is the medical term for moles. A small number of moles will never turn into cancer, but the presence of many (more than 100) or atypical moles indicates an increased individual risk of developing melanoma.

An atypical mole is defined as a mole that exhibits at least 3 of the following “ABCD” characteristics:
Asymmetry in its shape
Irregular or unclear contour
Color that varies from one area to another
Increase in diameter
Dynamic evolution of size and shape over time

Congenital moles are moles that are present from birth. Large (>5 cm) congenital moles have an increased risk of turning into melanoma.
Sun exposure: natural exposure to ultraviolet (UV) radiation emitted by the sun is a significant risk factor for developing melanoma.

If we were to describe people with the highest risk of developing melanoma, they have:

Fair skin, especially those with red or blond hair and blue or green eyes.
Sun-sensitive skin that rarely tans and burns easily (Fritzpatrick phototype I).
More than 50 moles with an unusual appearance (dysplastic nevus syndrome).
History of severe sunburn or prolonged exposure to the sun or solarium.
Family or medical history. If there is a family history or a history of skin cancer or other melanoma in the patient himself, the chances of developing melanoma increase.
Weakened immune system. Patients suffering from AIDS or lymphoma, who have undergone a transplant or chemotherapy, or who have been exposed to excessive sun are at increased risk of melanoma.

To diagnose melanoma, a biopsy is required, in which a piece of skin is removed for histopathological analysis. Whenever possible, it is best to remove the entire lesion within 2 cm. Mapping moles with special equipment and dermatoscopy are the best prevention for melanoma.

In any case of melanoma, for the choice of continuation in treatment, the role of the biopsy results, CT and hematological results is essential. After the biopsy results, the disease is staged.

The biopsy results should include:

Maximum thickness or Breslow thickness
Maximum thickness shows how deep the tumor has penetrated the skin and is measured in millimeters (mm). The greater the thickness, the worse the prognosis.
Mitotic activity shows how quickly the melanoma cells are dividing. The division of a cell into two new cells is called mitosis. The pathologist counts under a microscope how many cells are dividing in 1mm2 1 or more cells are dividing per mm2, the prognosis is worse than if there are less than 1 cell per mm2.
Presence or absence of ulceration
Ulceration means that the melanoma has invaded the underlying skin
Presence and extent of tumor regression
In some cases, the pathologist sees signs that the tumor has regressed in certain areas of the biopsy. This is called tumor regression and means that, in the past, the tumor was larger. Unfortunately, it is a poor prognostic factor.
Positive or negative surgical resection margins*
The pathologist checks whether the entire tumor has been removed by analyzing whether it is completely surrounded by normal tissue (a term given as “within healthy margins”).
Lymphatic infiltration
Finding cancer cells/emboli in the vessels means that the cancer cells have probably spread to the lymph nodes, or to other organs, that is, the original tumor has metastasized.
Tumor infiltration by lymphocytes *
The presence of lymphocytes in the tumor is usually associated with a better prognosis.
Detection of the presence of mutation(s) in the cancer cells (mutational test). Presence or absence of mutation of the BRAF or NRAS gene, c-kit. If the gene is mutated, the initiation of targeted therapy is recommended.

While melanoma is one of the most dangerous forms of skin cancer, promising new treatment options improve the quality of life and increase survival rates for patients with advanced melanoma.

Treatment options depend on the stage of the disease, the location of the tumor, and the patient’s overall health. Options include:

Surgical removal of the melanoma
Immunotherapy
Targeted therapy
Chemotherapy
Radiation
Regional chemotherapy with vascular blockade

Surgical removal

Stage 0 «in situ» and stage I
Tumors discovered at an early stage are limited to the upper layers of the skin and have no evidence of spread. These melanomas are treated with surgical excision. Usually, this is the only treatment needed. The first step was a biopsy, where the doctor removed part or all of the lesion and sent it to a laboratory for analysis, where the melanoma was diagnosed and staged. For excisional surgery, the surgeon removes more tissue from the site within 2 cm.

Stage II
Because the risk of spread to local lymph nodes is higher in stage II melanomas, a sentinel lymph node biopsy is often recommended in addition to surgery to remove the original tumor. If melanoma is found in the sentinel node, your doctor may examine the remaining nodes in that lymph basin and remove any that contain cancer cells. After surgery, additional treatment may be recommended.

Stage III and Stage IV
Advanced melanomas are those that have spread beyond the original tumor, more often reaching lymph nodes and/or distant organs and becoming more difficult to treat.

In recent years, new immunotherapies and targeted therapies have achieved positive results in many patients with stage III and IV melanoma.

These treatments work by shrinking tumors and inhibiting or slowing the progression of the disease to help extend life by months to years and perhaps even lead to a cure.

Immunotherapy

Immunotherapy boosts the body’s ability to fight melanoma and other cancers by using synthetic versions of natural immune system proteins or by allowing the release of cells that attack tumors. These treatments are effective when used alone or in combination.

Immune checkpoint inhibitors

Immune checkpoint inhibitors (also known as checkpoint blockade therapy) are given intravenously to melanoma patients to stop checkpoint molecules from inhibiting T cells. This allows the immune system to release waves of T cells to attack and kill cancer cells.

The following checkpoint inhibitors are used for patients with advanced melanoma:

HOW IT WORKS

Tumor-infiltrating lymphocytes (TILs) are natural immune system cells that can recognize unique tumor markers on cancer cells in the body and attack and kill them. This treatment, called autologous tumor-derived T cell immunotherapy, is designed to boost the patient’s own TILs outside the body and then deliver them back to the patient to attack cancer cells.

Combination Immunotherapy

First-of-its-kind Results from Paired Therapies

Nivolumab-Ipilimumab (Opdivo® – Yervoy®)
Nivolumab-Relatlimab (Opdualag®), Combination

Oncolytic Virus Therapy

Talimogene laherparepvec, or T-VEC (Imlygic®)

Early Immunotherapies

Older forms of immunotherapy that were once used in patients with high-risk stage II, III, and IV melanoma have since been replaced as first-line treatments by newer, more effective treatment options.

Interferon alfa-2b
Interleukin-2
Pegylated interferon alfa-2b

Targeted therapies

Targeted therapies use drugs and other agents to attack melanoma by blocking the action of faulty genes and molecules – including BRAF and MEK – that play a role in accelerating the growth and spread of melanoma cells. When successful, these treatments stop or slow the progression of the disease and help patients live longer.

BRAF Inhibitors

Vemurafenib (Zelboraf®)
Dabrafenib (Tafinlar®)
Encorafenib (Braftovi®)

MEK Inhibitors

Trametinib (Mekinist®)
Cobimetinib (Cotellic®)
Binimetinib (Mektovi®)

Chemotherapy

Treatment overview

Since immunotherapies and targeted therapies produce vastly superior results, chemotherapy is no longer a first-line treatment. It is most often used if targeted therapies and/or checkpoint blockade therapies fail. It may sometimes be used in combination with these other treatments.

Radiation therapy

Radiation is rarely used to treat a primary melanoma tumor, but it can be used to treat melanomas that have spread to the brain or other distant sites to shrink tumors and reduce pain, improve comfort, and improve mobility. It can also be used at the surgical site after surgery to ensure that all cancer cells have been killed and is being studied in combination with therapies such as checkpoint blockade therapies to improve outcomes.

Regional administration of chemotherapy to the limb (HILP – Hyperthermic Isolated Limb Perfusion). This treatment method is also approved by internationally recognized protocols for the treatment of malignant diseases

After surgery, monitoring of progress is required for 10 years. Initially, re-examination is recommended every 3 months for the first year, then every 6 months for the next 2 years, and finally, annually. The doctor will inform us when we should go for a re-examination and monitoring.

Life expectancy depends on the stage of the disease and the type of melanoma. When diagnosed at an early stage, the five-year life expectancy is 98%, if lymph nodes are also affected it is 64% and if there are metastases to other organs it is 23%. The most common metastases from melanoma are to the liver and the brain.