by Jason Wasserman MD PhD FRCPC, reviewed on March 5, 2020
The thyroid is a small U-shaped gland located in the front of the neck. It is made up of two halves, called lobes, which lie along the trachea and are joined together by a narrow band of thyroid tissue, known as the isthmus.
The function of the thyroid gland is to take iodine, found in many foods, and convert it into thyroid hormone. Once made, the thyroid hormone is released into the blood stream and transported throughout the body where they control the body’s metabolism (e.g. the conversion of oxygen and calories to energy).
Most of the cells in the thyroid gland are called follicular cells. The follicular cells connect together to form small round structures called follicles. On the outside of the follicles are small specialized cells called C cells or parafollicular cells. The C cells make a hormone called calcitonin. Calcitonin is very important because it helps the body regulate the level calcium in the blood. C cells are a type of neuroendocrine cell because they come from the body’s nervous system and travel to the thyroid gland before we are born.
Compared to the number of follicular cells, there are very few C cells in the normal thyroid gland. For this reason, pathologists usually have to look very closely at the thyroid gland under the microscope before they find any C cells.
Medullary thyroid carcinoma is a type of thyroid cancer that starts from the C cells normally found in the thyroid gland. Like normal C cells, the abnormal C cells in medullary thyroid carcinoma make calcitonin. Pathologists perform a test called immunohistochemistry to ‘see’ the calcitonin inside the tumour cells. Your doctor may also perform a blood test which may show an abnormally high level of calcitonin in your blood.
For most patients diagnosed with medullary thyroid carcinoma, the cause remains unknown although a combination of genetic changes and environmental factors probably plays a role. Some patients, however, are born with specific genetic changes that are known to cause medullary thyroid carcinoma. Because these genetic changes can also cause other types of tumours, they are called a syndrome.
The most common syndrome associated with medullary thyroid carcinoma is multiple endocrine neoplasia (MEN). There are three types of MEN syndrome (numbered 1, 2, and 4) and medullary thyroid carcinoma is more likely to develop in patients with type 2.
Multiple endocrine neoplasia is caused by mutations in the genes MEN, RET, or CDKN1B. These genes provide information to the cell to tell it when to grow and divide to create new cells. A mutation is a change in the gene that prevents it from working normally. Cells with the abnormal gene grow and divide much faster than normal cells. Over time this results in the development of a tumour made of C cells.
Patients with MEN syndrome are at high risk for developing medullary thyroid carcinoma. For this reason, all patients with MEN syndrome should be referred to doctor specializing in thyroid cancer.
The diagnosis of medullary thyroid carcinoma can be made after a small sample of thyroid tissue is removed in a procedure called a fine needle aspiration or after part of all of the thyroid gland is surgically removed.
When examined under the microscope, the tumour cells in medullary thyroid carcinoma can range in size and shape from small and round to long and thin. This variety means that medullary thyroid carcinoma can sometimes look like another type of tumour. In order to make the correct diagnosis, pathologists will often perform additional tests such as immunohistochemistry.
Immunohistochemistry allows pathologists to learn more about the proteins inside a cell. A cell that makes a specific protein is called positive or reactive while a cell that does not make the protein is called negative or non-reactive.
When immunohistochemistry is performed on medullary thyroid carcinoma, the tumour cells typically show the following results:
Pathologists can also recognize medullary thyroid carcinoma because it produces a substance called amyloid which can be seen under the microscope. Amyloid is caused by the build up of abnormal proteins in the body. In the case of medullary thyroid carcinoma, the amyloid is made up of large amounts of calcitonin produced by the tumour cells. Pathologists perform a special stain called Congo red which allows them to more easily see the amyloid.
When examined under the microscope, normal C cells are hard to find without the use of special tests such as immunohistochemistry. C cell hyperplasia means that there are an increased number of C cells in the thyroid gland outside of the tumour. The increased number of C cells usually look like large groups of cells sitting beside a follicle.
Why is this important? C cell hyperplasia is associated with an increased risk for developing medullary thyroid carcinoma and is more common in patients with a genetic syndrome such as multiple endocrine neoplasia (MEN). Patients with medullary thyroid carcinoma and C cell hyperplasia should be referred to a medical geneticist for counselling.
This is the size of the tumour measured in centimeters (cm). Tumour size will only be described in your report after the entire tumour has been removed. The tumour is usually measured in three dimensions but only the largest dimension is described in your report. For example, if the tumour measures 4.0 cm by 2.0 cm by 1.5 cm, your report will describe the tumour as being 4.0 cm.
Why is this important? Tumour size plays an important role in determining the pathologic tumour stage for medullary thyroid carcinoma (see Pathologic stage below). Large tumours are more likely to spread to other parts of the body. However, even small tumours (1 cm or less) are associated with a 20% risk of spreading to lymph nodes and other parts of the body.
A microcarcinoma is a tumour that measures less than 1.0 cm in size. A microcarcinoma may be the only tumour found in the thyroid gland or it may be found in the thyroid gland outside of a larger tumour.
Why is this important? It is not uncommon to find more than one medullary microcarcinoma in a person with a genetic syndrome such as multiple endocrine neoplasia (MEN).
It is not unusual for more than one tumour to be found in the same thyroid gland. If more than one tumour is found, each tumour will be described separately in your pathology report. Pathology report will often use the word multifocal to describe a thyroid gland with multiple tumours.
Why is this important? When more than one tumour is found, only the largest tumour is used to determine the pathologic tumour stage (see Pathologic stage below).
Extrathyroidal extension means the cancer cells have spread beyond the normal thyroid gland into the surrounding tissue. Cancer cells can also spread directly into nearby organs such as muscles, the esophagus, or the trachea.
There are two types of extrathyroidal extension:
Why is this important? Macroscopic (gross) extrathyroidal extension increases the tumour stage (see Pathologic stage below) and is associated with worse prognosis. Microscopic extrathyroidal extension does not change the tumour stage.
Blood vessels carry blood around the body. Cancer cells that enter a blood vessel are able to travel to distant parts of the body such as the lungs and bones. The movement of cancer cells to a different part of the body is called metastasis.
Cancer cells seen inside of a blood vessel is called vascular invasion or angioinvasion. If vascular invasion is seen, your pathologist will count the number of vessels that contain cancer cells.
Your report will describe vascular invasion as negative if no cancer cells are seen inside of a blood vessel, positive and focal if there are less than 4 blood vessels with cancer cells, and positive an diffuse if there are 4 or more blood vessels with cancer cells.
Why is this important? Vascular invasion is important because cancer cells that enter a blood vessel are more likely to spread to other parts of the body.
Lymphatics are small thin vessels that provide a way for fluids and cells to leave a tissue. Lymphatics are found all over the body. Cancer cells that enter a lymphatic vessel are able to spread to other parts of the body, in particular lymph nodes.
Cancer cells seen inside a lymphatic vessel is called lymphatic invasion. Your pathologist will carefully examine your tissue for lymphatic invasion. If lymphatic invasion is seen, it will be called positive. If no lymphatic invasion is seen, it will be called negative.
Why is this important? Lymphatic invasion is important because cancer cells that enter a lymphatic space are more likely to spread to lymph nodes or other parts of the body.
A margin is the tissue that has to be cut by the surgeon to remove the thyroid gland from your body. A margin is considered positive when there are cancer cells at the very edge of the cut tissue. A negative margin means there were no cancer cells seen at the cut edge of the tissue.
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 Lymphatic invasion above). The movement of cancer cells from the tumour to a lymph node is called a metastasis.
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 are numbered 1 through 7. 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.
Your pathologist will carefully examine each lymph node for cancer cells. Lymph nodes that contain cancer cells are often called positive while those that do not contain any cancer cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain cancer cells.
Why is this important? Finding cancer cells in one or more lymph nodes increases the nodal stage (see Pathologic stage below) and is associated with worse prognosis.
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.
All lymph nodes are surrounded by a thin rim of tissue called a capsule. Extranodal extension (ENE) means that cancer cells have broken through the capsule and into the tissue that surrounds the lymph node.
The pathologic stage for medullary thyroid carcinoma 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 worse prognosis.
The pathologic stage will only be included in your report after the entire tumour has been removed. It is not included in your report after a biopsy or fine needle aspiration.
Medullary thyroid carcinoma is given a tumour stage between 1 and 4 based on the size of the tumour and the presence of cancer cells outside of the thyroid (see Extrathyroidal extension above).
Medullary thyroid carcinoma is given a nodal stage of 0 or 1 based on the presence or absence of cancer cells in a lymph node and the location of the involved lymph nodes.
Medullary thyroid carcinoma 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 sent for pathological examination. Because this tissue is rarely sent, the metastatic stage cannot be determined and is listed as MX.