Medullary thyroid carcinoma

by Jason Wasserman MD PhD FRCPC
July 12, 2024

Medullary thyroid carcinoma is a rare type of thyroid cancer originating from the C cells (parafollicular cells) of the thyroid gland. These cells produce a hormone called calcitonin, which helps regulate calcium levels in the blood. Medullary thyroid carcinoma accounts for about 1-2% of all thyroid cancers.

What are the symptoms of medullary thyroid carcinoma?

Symptoms of medullary thyroid carcinoma can vary but often include:

• A lump or nodule in the neck.
• Swelling in the neck.
• Difficulty swallowing.
• Changes in voice or hoarseness.
• Persistent cough not associated with a cold.
• Diarrhea (in some cases due to high levels of calcitonin).
• Flushing of the face.

What causes medullary thyroid carcinoma?

The exact cause of medullary thyroid carcinoma is not always clear, but it can occur sporadically or as part of a genetic syndrome. Sporadic medullary thyroid carcinoma, which is not inherited, accounts for about 75-80% of cases. The remaining 20-25% are associated with genetic syndromes.

Genetic syndromes are associated with medullary thyroid carcinoma

Medullary thyroid carcinoma is often linked to genetic mutations, which are changes in the DNA sequence of the C cells in the thyroid gland. The most common mutations occur in the RET proto-oncogene. A proto-oncogene is a normal gene that can become an oncogene due to mutations, leading to cancer.

The following genetic syndromes are associated with medullary thyroid carcinoma:

• Multiple endocrine neoplasia type 2A (MEN2A): Patients with MEN2A are at high risk for developing medullary thyroid carcinoma, pheochromocytoma (a type of adrenal gland tumour), and parathyroid adenomas.
• Multiple endocrine neoplasia type 2B (MEN2B): Patients with MEN2B are at high risk for developing medullary thyroid carcinoma and pheochromocytoma. Patients also have distinctive physical features such as mucosal neuromas and marfanoid body habitus.
• Familial medullary thyroid carcinoma (FMTC): FMTC is a variant of MEN2A. Patients with FMTC are at increased risk for developing medullary thyroid carcinoma but not the other endocrine tumours associated with MEN2A.

Molecular alterations in medullary thyroid carcinoma

Medullary thyroid carcinoma, like many cancers, often involves changes in the DNA of the C cells. These changes allow the cells to grow faster and under less control than normal cells.

Common molecular changes in medullary thyroid carcinoma include:

• RET mutations: Mutations in the RET proto-oncogene are the most common genetic alterations in medullary thyroid carcinoma. These mutations are found in both sporadic and hereditary cases. RET mutations can lead to more aggressive tumour behaviour and are often used to guide treatment decisions.
• RAS mutations: Mutations in the RAS gene family are less common but can also be present in medullary thyroid carcinoma. RAS mutations are generally associated with a less aggressive form of the disease than RET mutations.
• Gene fusions: Rarely, gene fusions involving RET or other genes can occur in medullary thyroid carcinoma. These fusions can contribute to cancer development and progression.

Microscopic features of this tumour

Under the microscope, medullary thyroid carcinoma has distinct features. The tumour cells can appear round, polygonal (many-sided), or spindle-shaped (long and thin). These cells often grow in various patterns, including nests (clusters of cells), trabeculae (cords of cells), or a diffuse pattern where cells spread out evenly. Another characteristic feature of medullary thyroid carcinoma is amyloid deposition. Amyloid is a protein that accumulates in the spaces between the tumour cells and can be seen as pink, amorphous (shapeless) material when stained and viewed under the microscope.

Immunohistochemistry

Immunohistochemistry (IHC) is a laboratory test that uses special antibodies to detect specific proteins in tissue samples, helping to identify different types of cells based on the proteins they express. In diagnosing medullary thyroid carcinoma, immunohistochemistry detects the presence of calcitonin and other markers produced by parafollicular cells, confirming the tumour’s origin. This test helps pathologists accurately diagnose medullary thyroid carcinoma and distinguish it from other types of thyroid cancer.

Typical immunohistochemistry results for medullary thyroid carcinoma:

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

Histologic grade

In your pathology report for medullary thyroid carcinoma, you might see a mention of the cancer’s histologic grade. This grading helps doctors understand how aggressive the cancer is and decide on the best treatment plan. The grade can only be determined after the tumour is examined under a microscope by a pathologist.

There are two grades for medullary thyroid carcinoma: low grade and high grade. Compared to low grade tumours, high grade tumours are more likely to spread to other body parts and are associated with decreased overall survival.

Low grade medullary thyroid carcinoma:

• Mitotic index: This is a measure of how many cells are dividing. In low grade medullary thyroid carcinoma, there are fewer than 5 dividing cells per 2 square millimetres of tissue.
• Ki67 proliferative index: The Ki-67 proliferative index is another way to measure cell division. In low grade medullary thyroid carcinoma, fewer than 5% of the cells are actively dividing.
• Tumour necrosis: This means areas of dead cancer cells. Low grade medullary thyroid carcinoma does not have any areas of tumour necrosis.

High grade medullary thyroid carcinoma

High grade medullary thyroid carcinoma is more aggressive and has at least one of the following features:

• Mitotic index: There are 5 or more dividing cells per 2 square millimetres of tissue.
• Ki67 proliferative index: 5% or more of the cells actively divide.
• Tumour necrosis: There are areas of dead cancer cells present.

Tumour size

After the tumour is removed completely, it will be measured. 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 it as being 4.0 cm. Tumour size is important for medullary thyroid carcinoma because it determines the pathologic tumour stage (pT) and because larger tumours are more likely to spread to other body parts, such as lymph nodes.

Extrathyroidal extension

​Extrathyroidal extension (ETE) refers to the spread of cancer cells beyond the thyroid gland into surrounding tissues. It is an important prognostic factor in thyroid cancer, as it can significantly influence both the staging and management of the disease.

Extrathyroidal extension is classified into two types based on the extent of the spread:

• Microscopic extrathyroidal extension: This form of extension is only visible under a microscope and indicates that the cancer has spread just beyond the thyroid capsule but cannot be seen with the naked eye. It may involve minimal infiltration into surrounding soft tissues.
• Macroscopic (or gross) extrathyroidal extension: This type is visible to the naked eye or detectable during surgery. It involves more obvious and extensive invasion into neighbouring structures such as muscles, trachea, esophagus, or major blood vessels.

Extrathyroidal extension is important for the following reasons:

• Prognosis: Macroscopic (gross) extrathyroidal extension is associated with a worse prognosis. It suggests a more aggressive cancer that is more likely to recur and metastasize.
• Staging: Extrathyroidal extension impacts the staging of thyroid cancer. For instance, in the TNM (Tumor, Node, Metastasis) classification system used for thyroid cancer, macroscopic extrathyroidal extension results in a higher pathologic tumour stage (pT).
• Treatment and follow-up: The presence of macroscopic (gross) extrathyroidal extension might lead to more aggressive treatment strategies and closer follow-up to reduce the risk of recurrence.

Vascular invasion (angioinvasion)

Vascular invasion (also known as angioinvasion) in the context of medullary thyroid carcinoma of the thyroid gland refers to the spread of cancer cells into blood vessels outside the tumour. Vascular invasion is a marker of more aggressive behaviour and has important implications for the prognosis and management of the cancer.

Importance of vascular invasion:

• Metastatic potential: Vascular invasion increases the risk of cancer cells spreading to distant sites in the body through the bloodstream. This can lead to the formation of metastases, especially in organs like the lungs and bones, which are common sites for thyroid cancer metastasis.
• Prognosis: The presence of vascular invasion is generally associated with a poorer prognosis. It indicates that the cancer is more aggressive and capable of spreading to distant parts of the body.
• Treatment decisions: Identifying vascular invasion can influence treatment decisions. For instance, it may lead to the use of higher doses of radioactive iodine or the inclusion of systemic therapies to address potential metastatic disease.
• Follow-up and monitoring: Given their higher risk profile, patients with evidence of vascular invasion may require closer follow-up and more intensive monitoring for recurrence or spread of the disease.

Lymphatic invasion

Lymphatic invasion in the context of medullary thyroid carcinoma of the thyroid gland refers to the infiltration and spread of cancer cells into the lymphatic system. Cancer cells that enter the lymphatic system can travel to lymph nodes. It is very common to find lymphatic invasion with papillary thyroid carcinoma, and unlike vascular invasion, the presence of lymphatic invasion is not necessarily associated with a more aggressive disease or a worse prognosis.

Margins

​​In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some tumour cells may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Lymph nodes

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small lymphatic vessels. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body, such as a lymph node, is called metastasis.

Cancer cells typically spread first to lymph nodes close to the tumour, although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node.

A neck dissection is a surgical procedure performed to remove lymph nodes from the neck. The lymph nodes removed usually come from different neck areas, 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.

If any lymph nodes are removed from your body, they will be examined under the microscope by a pathologist, and the examination results will be described in your report. “Positive” means that cancer cells were found in the lymph node. “Negative” means that no cancer cells were found. If cancer cells are found in a lymph node, the size of the largest group of cancer cells (often described as “focus” or “deposit”) may also be included in your report. Extranodal extension means that the tumour cells have broken through the capsule on the outside of the lymph node and have spread into the surrounding tissue.

The examination of lymph nodes is important for two reasons. First, this information determines the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment, such as radioactive iodine, chemotherapy, radiation therapy, or immunotherapy, is required.

Pathologic stage (pTNM)

​​The pathologic stage for medullary thyroid carcinoma is based on the TNM staging system, an internationally recognized system 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)

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)

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.

Other helpful resources

American Thyroid Association (ATA)

American Cancer Society

Learn more pathology

Atlas of Pathology