Invasive melanoma of the skin

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What is invasive melanoma?

Invasive melanoma is a type of skin cancer. The tumour is made up of specialized cells called melanocytes. Invasive melanoma typically starts in the skin although it can start in other sites such as the inside of the eye, mouth, nasal cavity, or esophagus. In the skin, melanoma is associated with excessive sun exposure especially multiple severe sunburns.

Skin

Skin is made up of three layers: epidermis, dermis, and subcutaneous fat. The surface and the part you can see when you look at your skin is called the epidermis. The cells that make up the epidermis include squamous cells, basal cells, melanocytes, Merkel cells, and cells of the immune system. The squamous cells in the epidermis produce a material called keratin which makes the skin waterproof and strong and protects us from toxins and injuries.

The dermis is directly below the epidermis. The dermis is separated from the epidermis by a thin layer of tissue called the basement membrane. The dermis contains blood vessels and nerves. Below the dermis is a layer of fat called subcutaneous adipose tissue.

Melanocytes

Melanocytes are small cells that produce melanin, a dark pigment that helps protect our skin from the sun’s ultraviolet rays. The amount of melanin normally found in our skin determines our skin colour. People with very light skin produce very little melanin while people with very dark skin produce a lot of melanin.

 

How do pathologists make this diagnosis?

The diagnosis of melanoma can only be made after a tissue sample is examined under a microscope by a pathologist. A small tissue sample is usually removed in a procedure called a biopsy. After the diagnosis is made, your doctor will talk with you about the need to perform a second procedure to remove the rest of the tumour. This second procedure is called an excision.

Under the microscope, the melanocytes in melanoma are larger and darker than normal melanocytes. In order to make the diagnosis of melanoma, abnormal melanocytes must be seen in both the epidermis and the dermis below. The movement of abnormal melanocytes from the epidermis into the dermis is called invasion.

Types of invasive melanoma

There are different types of invasive melanoma based on the size and shape of the cancer cells and the way the cancer cells stick together as the tumour grows. The type of melanoma can only be determined after the tumour has been examined under a microscope by a pathologist.

The most common types of melanoma are:

• Superficial spreading – When examined under the microscope, most of the tumour is growing just below the epidermis. Less tumour is seen growing downward into the dermis.
• Nodular – This type of melanoma is the opposite of the superficial spreading type. When examined under the microscope, most of the tumour is growing down into the epidermis. Less of the tumour is seen growing just under the epidermis.

The type of melanoma is important because some types, such as the superficial spreading type, are less likely to spread to lymph nodes or other parts of the body. The movement of cancer cells from the tumour to another part of the body is called metastasis.

What to look for in your  report after the tumour has been removed

Tumour size​

After the tumour has been removed fully, your pathologist will measure it in three dimensions although only the largest dimension is typically included in your report. For example, if the tumour measures 5.0 cm by 3.2 cm by 1.1 cm, the report may describe the tumour size as 5.0 cm in the greatest dimension.

Maximum tumour thickness (Breslow thickness)

All melanomas start in the epidermis on the surface of the skin. The tumour thickness or Breslow thickness describes how far the cancer cells have travelled from the epidermis into the tissue below. The movement of cancer cells from the epidermis into the tissue below is called invasion. The tumour thickness is measured from the surface of the skin to the deepest point of invasion. The maximum tumour thickness is measured in millimetres.

The tumour thickness or Breslow thickness is the most important prognostic factor and it is used to determine the tumour stage (see Pathological stage below). Thicker tumours are more likely to spread to lymph nodes or other parts of the body. The spread of cancer cells outside of the tumour is called metastasis.

Ulceration

An ulcer is an area of skin where the epidermis has been damaged. In an ulcer, the epidermis has been lost and the dermis below is exposed. An ulcer over a melanoma is associated with a worse prognosis and is also used to determine the tumour stage (see Pathological stage below).

Macroscopic satellite nodules

A macroscopic satellite nodule is a large group of cancer cells that are separated from the main tumour. These nodules are big enough to be seen without a microscope. If your tumour has macroscopic satellite nodules, this information will be is found under the gross description section of your pathology report.

Microsatellite tumour nodules

Microscopic satellite nodules are groups of cancer cells that can only be seen with a microscope.  Like macroscopic satellite nodules, microscopic nodules are separate from the tumour. Tumours with microscopic satellite nodules are more likely to be spread to a lymph node or distant body site. For that reason, microsatellite tumour nodules are associated with a worse prognosis.

Tumour infiltrating lymphocytes

Lymphocytes are specialized cells that are part of the body’s immune system. Lymphocytes respond to infections, injury, or cancer. Lymphocytes are frequently found in the tissue around melanoma and their presence is considered a sign that the body is attempting to prevent the spread of the disease.

There are two ways to describe the lymphocytes around the tumour:

• Brisk – This means that lots of lymphocytes were seen in and around the tumour.
• Non-brisk – This means that very few lymphocytes were seen around the tumour.

Tumours with non-brisk tumour infiltrating lymphocytes are more likely to spread to a lymph node or a distant part of the body such as the lungs.

Margins

A margin is the normal tissue that surrounds a tumour and is removed with the tumour at the time of surgery. In most cases, surgeons will try to remove 1 cm of normal tissue around the entire tumour.

The normal skin surrounding the tumour is called the peripheral margin while the tissue below the tumour is called the deep margin. Both margins are closely examined under the microscope for cancer cells in the normal-looking tissue.

If no cancer cells are seen at the cut edge of the tissue the margin is considered negative. If cancer cells are seen at the very edge of the cut tissue the margin is considered positive. A positive margin is associated with an increased risk that the tumour will come back in the same location after surgery (local recurrence).

Mitotic rate

Cells divide in order to create new cells. This process is called mitosis. Pathologists frequently count the number of mitoses in a tumour and this count is called the mitotic rate. Most pathology reports describe the mitotic rate as the number of mitotic cells per millimetre square. The mitotic rate is only described for invasive melanoma. The mitotic rate is important because tumours with more mitotic figures are more likely to spread to lymph nodes or other parts of the body.

Lymphovascular invasion

Blood moves around the body through long thin tubes called blood vessels. Another type of fluid called lymph which contains waste and immune cells moves around the body through lymphatic channels. Cancer cells can use blood vessels and lymphatics to travel away from the tumour to other parts of the body. The movement of cancer cells from the tumour to another part of the body is called metastasis.

Before cancer cells can metastasize, they need to enter a blood vessel or lymphatic. This is called lymphovascular invasion. Lymphovascular invasion is important because it increases the risk that cancer cells will be found in a lymph node or a distant part of the body such as the lungs.

Perineural invasion (neurotropism)

Cancer cells wrapped around a nerve in the skin is called perineural invasion (neurotropism). Perineural invasion allows the cancer cells to travel out of the tumour and into the surrounding normal tissue.

Perineural invasion makes it harder for your doctor to fully remove the tumour. For that reason, perineural invasion is associated with a higher risk that the tumour will re-grow in the same site (local recurrence) after treatment.

Tumour regression

Tumour regression is the partial or complete disappearance of the main tumour and is usually assumed to be a result of the body’s immune system attacking the cancer cells. The presence of tumour regression however does not mean that the cancer is gone and cancer cells may still travel to other parts of the body.

Tumour regression can only be identified after microscopic examination of the tissue and will be described as partial if some cancer cells are still seen or complete if there are no cancer cells left in the area where the tumour was previously located.

Lymph nodes

Lymph nodes are small immune organs located throughout the body. Cancer cells can travel from the tumour to a lymph node through lymphatic channels located in and around the tumour (see Lymphovascular invasion above). The movement of cancer cells from the tumour to a lymph node is called metastasis.

If your tumour was located on your face or head, lymph nodes from the neck are sometimes removed at the same time as the main tumour in a procedure called a neck dissection. The lymph nodes removed usually come from different areas of the neck and each area is called a level. The levels in the neck include 1, 2, 3, 4, and 5. Your pathology report will often describe how many lymph nodes were seen in each level sent for examination.

Lymph nodes on the same side as the tumour are called ipsilateral while those on the opposite side of the tumour are called contralateral.

A sentinel lymph node is the closest lymph node to the tumour. When the cancer cells in melanoma travel to a lymph node, they usually go to the sentinel node first. All other lymph nodes in the area of the tumour are simply referred to as regional lymph nodes. Your pathology report will specify which lymph nodes are involved.

Most reports include the total number of lymph nodes examined and the number that contains cancer cells. Lymph nodes that contain cancer cells are often called positive while those that do not contain any cancer cells are called negative.

Tumour deposit

A group of cancer cells inside of a lymph node is called a tumour deposit. If a tumour deposit is found, your pathologist will measure the deposit and the largest tumour deposit found will be described in your report.

Types of tumour deposits:

• Isolated tumour cells – Individual cells not forming groups.
• Micro-deposit – Small groups of tumour cells.
• Macro-deposit – Large groups of tumour cells that may fill up the entire lymph node.

Macro-deposits are associated with a worse prognosis. The size of the largest tumour deposit is also used to determine the nodal stage (see Pathologic stage below).

Extranodal extension (ENE)

All lymph nodes are surrounded by a capsule. Extranodal extension (ENE) means that cancer cells have broken through the capsule and into the tissue that surrounds the lymph node. Extranodal extension is important because it is associated with a higher risk of new tumours developing in the neck and is often used by your doctors to guide your treatment. Extranodal extension is also used to determine the nodal stage (see Pathologic stage below).

Pathologic stage

​The pathologic stage for melanoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means more advanced disease and a worse prognosis.

Tumour stage (pT) for invasive melanoma

Invasive melanoma is assigned a tumour stage between 1 and 4 based on the maximum tumour thickness (Breslow thickness) and the presence or absence of ulceration. In general tumours with a greater thickness or ulceration receive a higher tumour stage.

Nodal stage (pN) for invasive melanoma

Invasive melanoma is given a nodal stage of 0 to 3 based on the presence of cancer cells in a lymph node, the number of lymph nodes involved, and the presence of tumour satellites.

If no lymph nodes are involved the nodal stage is N0. If no lymph nodes are sent for pathological examination, the nodal stage cannot be determined and the nodal stage is listed as NX.

Metastatic stage (pM) for invasive melanoma

Melanoma is given a metastatic stage of 0 or 1 based on the presence of cancer cells at a distant site in the body (for example the lungs). The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as MX.

Molecular tests

Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. Because the instructions are very long, they are broken up into sections called genes and each gene tells the cell how to produce a piece of the machine called a protein.

If the DNA becomes damaged or if it cannot be read accurately, the cell will be unable to produce the proteins it requires to function normally. An area of damaged DNA is called a mutation and mutations are one of the most common causes of cancer in humans.

It is common for melanoma to contain mutations. These mutations involve genes that allow melanoma cancer cells to grow faster than normal cells.

Your tissue will be automatically tested for mutations if any of the following conditions are met:

• The tumour is very thick (Breslow thickness).
• The surface of the tumour is ulcerated.
• Cancer cells are found in a lymph node.
• Cancer cells have spread to a distant organ.

In many hospitals, pathologists perform molecular tests to look for mutations in the following genes:

• BRAF
• CKIT
• GNAQ
• NRAS

The results of the molecular tests may be included with your main pathology report or they may be included in a separate molecular pathology report. Your report will say which genes were tested and if a mutation was found in any of the genes. If a mutation was found, the specific type of mutation may be described.

Your doctors will use these results to select medications that are specifically designed for the genetic changes identified in your tumour.

by Allison Osmond, MD FRCPC (updated September 9, 2021)