Medullary thyroid carcinoma

by Jason Wasserman MD PhD FRCPC
April 25, 2023


What is medullary thyroid carcinoma?

Medullary thyroid carcinoma is a type of thyroid cancer. The tumour starts from specialized C cells normally found in the thyroid gland.

Anatomy thyroid gland

What are C cells?

C cells (also called parafollicular cells) are a type of neuroendocrine cell that make a hormone called calcitonin. Calcitonin is very important because it helps the body regulate the level of calcium in the blood. C cells are found throughout the thyroid gland as single cells or in small groups.

C cells

What are the symptoms of medullary thyroid carcinoma?

The most common symptom of medullary thyroid carcinoma is a painless lump in the neck. Like normal C cells, the C cells in medullary thyroid carcinoma make a hormone called calcitonin. The increased production of calcitonin by the tumour can cause some patients to have low levels of calcium in their blood. Patients with increased calcitonin levels may experience symptoms such as diarrhea and flushing.

What causes medullary thyroid carcinoma?

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.

People with MEN syndrome are at high risk for developing medullary thyroid carcinoma. For this reason, all patients with MEN syndrome should be referred to a doctor specializing in the prevention and treatment of thyroid cancer.

How do pathologists make this diagnosis?

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 in a procedure called a resection.

What does medullary thyroid carcinoma look like under the microscope?

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.

medullary thyroid carcinoma
Medullary thyroid carcinoma. This picture shows a tumour made up of both round and spindle-shaped cells surrounded by pink amyloid.

When immunohistochemistry is performed on medullary thyroid carcinoma, the tumour cells typically show the following results:

  • Calcitonin – Positive.
  • PAX-8 – Negative.
  • TTF-1 – Positive.
  • CK7 – Positive.
  • Synaptophysin – Positive.
  • Chromogranin – Positive.
  • Thyroglobulin – Negative.

What is amyloid and why is it seen in medullary thyroid carcinoma?

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 highlights the amyloid.

What does C cell hyperplasia mean?

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 is 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.

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.

C cell hyperplasia

How is medullary thyroid carcinoma graded and why is the grade important?

Pathologists divide medullary thyroid carcinoma into two grades – low grade and high grade – based on three microscopic features: mitotic figures, Ki67 proliferative index, and necrosis.

  • Mitotic figures – A mitotic figure is a cell that is dividing to create a new cell. Your pathologist will look for mitotic figures inside the tumour and will describe the rate as the number per 2 mm square or 20 high-powered fields (areas of tissue examined with a high-powered lens).
  • Ki67 proliferative index- Ki67 is a marker used to identify cells that are able to divide to create new cells. The Ki67 proliferative index is the percentage of cells that express Ki67 in a specified area of tissue, typically 2 mm square or 20 high-powered fields.
  • Necrosis – Necrosis is a type of cell death. Tumours that are growing quickly are more likely to show areas of necrosis.
Low grade medullary thyroid carcinoma

Medullary thyroid carcinoma is called low grade when all of the following microscopic features are seen: less than 5 mitotic figures in an area measuring 2 mm square or 20 high-powered fields, Ki67 proliferative index less than 5%, and no necrosis.

High grade medullary thyroid carcinoma

Medullary thyroid carcinoma is called high grade when any one of the following microscopic features are seen: 5 or more mitotic figures in an area measuring 2 mm square or 20 high-powered fields, Ki67 proliferative index equal to or greater than 5%, or necrosis.

Why is the tumour size important for medullary thyroid carcinoma?

Most pathology reports will describe the size of the tumour, measured either in centimetres or millimetres. If more than one tumour is found, your pathology report may provide a size range or just describe the largest tumour. The tumour size is important because it is used to determine the pathologic tumour stage (pT) for medullary thyroid carcinoma. 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.

What does micromedullary thyroid carcinoma mean?

Some pathology reports will use the term “micro” to describe a medullary thyroid carcinoma if the tumour measures less than 1.0 cm in size. People with a genetic syndrome such as multiple endocrine neoplasia (MEN) are more likely to develop multiple micromedullary thyroid carcinomas.

​What does extrathyroidal extension mean and why is it important?

​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:

  • Microscopic – The cancer cells outside of the thyroid gland were only found after the tumour was examined under the microscope.
  • Macroscopic (gross) – The tumour can be seen growing into the surrounding tissues without the use of a microscope. This type of extrathyroidal extension may be seen by your surgeon at the time of surgery or by the pathologist’s assistant performing the gross examination of the tissue sent to pathology.

Macroscopic (gross) extrathyroidal extension increases the tumour stage (pT) and is associated with a worse prognosis. In contrast, microscopic extrathyroidal extension does not change the tumour stage.

What does vascular invasion (angioinvasion) mean and why is it important?

​Vascular invasion (also called angioinvasion) is the spread of tumour cells into a blood vessel. Blood vessels carry blood around the body. Tumour cells that enter a blood vessel are able to spread to distant parts of the body such as the lungs and bones.

Most reports will describe vascular invasion as negative if no tumour cells are seen inside a blood vessel or positive if tumour cells are seen inside at least one blood vessel. Vascular invasion is important because tumour cells that enter a blood vessel are more likely to spread to other parts of the body.

What does lymphatic invasion mean and why is it important?

​Lymphatic invasion means that tumour cells were seen inside a lymphatic vessel. Lymphatic vessels are small hollow tubes that allow the flow of a fluid called lymph from tissues to immune organs called lymph nodes. Lymphatic invasion is important because tumour cells can use lymphatic vessels to spread to other parts of the body such as lymph nodes or the lungs. If lymphatic invasion is seen, it will be called positive. If no lymphatic invasion is seen, it will be called negative.

What is a margin and why are margins important?

​A margin is the tissue that has to be cut by the surgeon to remove the tumour along with any normal tissue from your body. Pathologists examine all margins to see if there are any tumour cells at the cut edge of the tissue. A margin is considered positive when there are tumour cells at the very edge of the cut tissue. A negative margin means there were no tumour cells seen at the cut edge of the tissue. Margins can only be assessed after the entire tumour has been removed.

Margin

Were lymph nodes examined and did any contain cancer cells?

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

Lymph node

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.

What is a neck dissection?

Lymph nodes from the neck are sometimes removed at the same time as the thyroid 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.

What is a 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.

What does extranodal extension (ENE) mean?

All lymph nodes are surrounded by a thin layer of tissue called a capsule. Cancer cells that have spread to a lymph node can break through the capsule and into the tissue surrounding the lymph node. This is called extranodal extension (ENE). Extranodal extension does not change the pathologic stage but your doctors may use this information when deciding which treatment is best for you.

extranodal extension

What is the pathologic stage (pTNM) for medullary thyroid carcinoma?

​​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 a more advanced disease and a worse prognosis.

Tumour stage (pT) for medullary thyroid carcinoma

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 (extrathyroidal extension).

  • T1 – The tumour is less than or equal to 2 cm and the cancer cells do not extend beyond the thyroid gland.
  • T2 – The tumour is greater than 2 cm but less than or equal to 4 cm and the cancer cells do not extend beyond the thyroid gland.
  • T3 – The tumour is greater than 4 cm OR the cancer cells extend into the muscles outside of the thyroid gland.
  • T4 – The cancer cells extend to structures or organs outside of the thyroid gland including the trachea, larynx, or esophagus.
Nodal stage (pN) for medullary thyroid carcinoma

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.

  • N0 – No cancer cells were found in any of the lymph nodes examined.
  • N1a – Cancer cells were found in one or more lymph nodes from levels 6 or 7.
  • N1b – Cancer cells were found in one or more lymph nodes from levels 1 through 5.
  • NX – No lymph nodes were sent to pathology for examination.
​Metastatic stage (pM) for medullary thyroid carcinoma

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.

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