Your pathology report for medullary thyroid carcinoma

by Jason Wasserman MD PhD FRCPC
November 13, 2025

Medullary thyroid carcinoma is a rare type of thyroid cancer that starts in C cells, also called parafollicular cells, in the thyroid gland. The thyroid is a butterfly-shaped gland at the front of the neck that produces hormones regulating metabolism. Unlike most thyroid cancers, which originate in follicular cells that produce thyroid hormone, medullary thyroid carcinoma arises from C cells that produce calcitonin, a hormone that helps regulate calcium levels in the blood.

Medullary thyroid carcinoma accounts for about 1 to 2 percent of all thyroid cancers. It can occur as a single tumour or as multiple nodules in one or both lobes of the thyroid.

What are the symptoms of medullary thyroid carcinoma?

The symptoms of medullary thyroid carcinoma can vary depending on the size of the tumour and whether it has spread beyond the thyroid. Many people first notice a lump or nodule in the neck. Other symptoms include swelling in the neck, difficulty swallowing, changes in voice or hoarseness, and a persistent cough unrelated to a cold or other respiratory infection.

Because medullary thyroid carcinoma produces calcitonin and sometimes other hormones or hormone-like substances, some patients develop diarrhea and flushing of the face. These symptoms occur when hormone levels in the blood are very high.

Some people may have no symptoms at the time of diagnosis, and the tumour is only discovered during imaging or blood tests performed for other reasons.

What causes medullary thyroid carcinoma?

Medullary thyroid carcinoma can occur either sporadically (by chance) or as part of an inherited genetic syndrome.

The sporadic form, which is not inherited, accounts for about 75 to 80 percent of cases. It usually presents as a single nodule in the thyroid and is more common in adults without a family history of the disease.

The remaining 20 to 25 percent of cases are associated with genetic syndromes and are hereditary. These inherited forms result from changes in specific genes that are passed down from parent to child. People with hereditary medullary thyroid carcinoma tend to develop the cancer at a younger age and may have tumours in both lobes of the thyroid.

Genetic syndromes associated with medullary thyroid carcinoma

Medullary thyroid carcinoma is often associated with mutations in the RET proto-oncogene, a gene that normally regulates cell growth and development. When mutated, RET becomes overactive and can drive cancer growth. RET mutations can be found in both hereditary and some sporadic cases.

Inherited RET mutations cause a group of conditions called multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC).

  • Multiple endocrine neoplasia type 2A (MEN2A): People with MEN2A have a high risk of developing medullary thyroid carcinoma, pheochromocytoma (a tumour of the adrenal gland), and parathyroid adenomas, which can cause high calcium levels.

  • Multiple endocrine neoplasia type 2B (MEN2B): People with MEN2B have a high risk of medullary thyroid carcinoma and pheochromocytoma. They often exhibit characteristic physical features, such as mucosal neuromas (bumps on the lips and tongue) and a marfanoid body habitus, characterized by long limbs and a slender build.

  • Familial medullary thyroid carcinoma (FMTC): FMTC is a variant of MEN2A in which medullary thyroid carcinoma occurs in multiple family members but without the other endocrine tumours seen in MEN2A.

Because of these associations, people diagnosed with medullary thyroid carcinoma are often referred for genetic counselling and RET testing, and family members may also be offered testing.

How is this diagnosis made?

The diagnosis of medullary thyroid carcinoma is usually made after a thyroid nodule is identified and tissue is examined by a pathologist.

Clinical evaluation and imaging

Your doctor may discover a thyroid nodule during a physical examination or through imaging tests, such as an ultrasound, a CT scan, or an MRI. Blood tests may show elevated levels of calcitonin or carcinoembryonic antigen (CEA), which are often increased in medullary thyroid carcinoma.

Fine needle aspiration (FNA) and biopsy

The first step in diagnosis is often a fine needle aspiration (FNA) of the thyroid nodule. In this procedure, a thin needle is used to remove cells from the nodule for examination under a microscope. FNA can suggest medullary thyroid carcinoma, particularly if the cells exhibit certain features and the wash fluid contains elevated calcitonin levels.

However, FNA may not always give a definitive diagnosis, and sometimes the diagnosis is only confirmed after the entire thyroid or part of it is removed.

Microscopic examination

When biopsy material or a surgically removed thyroid gland is examined, the pathologist looks for characteristic features of medullary thyroid carcinoma.

If only a small sample (such as an FNA or core biopsy) is available, the pathologist may see a population of atypical cells with a neuroendocrine appearance and may recommend further testing and surgery.

When the entire tumour is removed, the pathologist can more fully characterize the tumour, describe its size, confirm medullary thyroid carcinoma, and assess features such as histologic grade, extrathyroidal extension, vascular invasion, margins, and lymph node involvement.

Immunohistochemistry

Immunohistochemistry (IHC) is a laboratory test that uses special antibodies to detect specific proteins in tumour cells. It is very helpful in confirming medullary thyroid carcinoma and distinguishing it from other types of thyroid cancer.

Typical immunohistochemistry results in medullary thyroid carcinoma include:

  • Calcitonin: Positive. This confirms origin from C cells.

  • TTF-1: Positive. This marker supports thyroid or lung origin.

  • CK7: Positive. Indicates epithelial cells.

  • Synaptophysin: Positive.

  • Chromogranin: Positive.

Synaptophysin and chromogranin are neuroendocrine markers that reflect the neuroendocrine nature of C cells.

Medullary thyroid carcinoma is typically negative for PAX8 and thyroglobulin, which helps distinguish it from papillary and follicular thyroid carcinomas that arise from follicular cells and usually express these markers.

Histologic grade

Histologic grade describes how aggressive a tumour appears under the microscope, based on the number of mitotic figures (dividing cells) and the presence of areas of necrosis (tumour cell death).

There are two histologic grades for medullary thyroid carcinoma: low grade and high grade.

Low grade medullary thyroid carcinoma shows the following features:

  • Mitotic index (a measure of dividing cells) is fewer than 5 mitoses per 2 square millimeters of tissue.

  • The Ki-67 proliferative index (a marker of the number of cells actively dividing) is less than 5 percent.

  • Tumour necrosis (areas of dead tumour cells) is absent.

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

  • Mitotic index of 5 or more mitoses per 2 square millimeters.

  • Ki-67 proliferative index of 5 percent or more.

  • Presence of tumour necrosis.

Compared to low grade tumours, high grade medullary thyroid carcinomas are more likely to spread and are associated with decreased overall survival. Histologic grade is therefore an important part of your pathology report.

Tumour size

After the tumour is completely removed, it is measured in three dimensions. The largest dimension is usually recorded in the report. For example, a tumour measuring 4.0 cm by 2.0 cm by 1.5 cm will be reported as 4.0 cm.

Tumour size is important because larger tumours are more likely to spread to lymph nodes or distant organs and influence the pathologic tumour stage (pT).

Extrathyroidal extension

Extrathyroidal extension refers to the spread of cancer cells beyond the thyroid gland into surrounding tissues and structures. It is an important prognostic factor and affects staging and management.

Extrathyroidal extension is classified as:

  • Microscopic extrathyroidal extension, which is seen only under the microscope. It indicates minimal spread, just beyond the thyroid capsule, into the surrounding soft tissues.

  • Macroscopic (gross) extrathyroidal extension, which is visible to the surgeon during the operation or seen on imaging. It involves a clear invasion into neighbouring structures, such as strap muscles (neck muscles), the trachea (windpipe), the esophagus (food pipe), or major blood vessels.

Macroscopic extrathyroidal extension is associated with a worse prognosis and typically leads to a higher tumour stage (pT). It may also lead to more aggressive treatment and closer follow-up.

Vascular invasion (angioinvasion)

Vascular invasion, also known as angioinvasion, occurs when cancer cells are found within blood vessels outside the primary tumour. This is a marker of more aggressive behaviour.

Vascular invasion is important because:

  • It increases the risk that cancer cells will travel through the bloodstream to distant sites, such as the lungs and bones.

  • It is associated with a poorer prognosis.

  • It may influence treatment decisions and follow-up, prompting more intensive monitoring for distant metastases.

Pathologists examine the tissue carefully for evidence of tumour cells within vessel walls or in the vessel spaces.

Lymphatic invasion

Lymphatic invasion means cancer cells have entered lymphatic channels, which are tubes that carry lymph fluid to lymph nodes. From these channels, cancer cells can travel to lymph nodes in the neck or upper chest.

Lymphatic invasion is commonly seen in thyroid cancers, including medullary thyroid carcinoma. Its presence suggests an increased risk of spread to lymph nodes, but unlike vascular invasion, it is not always associated with a dramatically worse prognosis. It is reported in the pathology report because it helps guide decisions about lymph node evaluation and follow-up.

Margins

Margins refer to the edges of tissue removed during surgery. The pathologist examines all margins to see if cancer cells are present at or near the cut edge.

  • A negative margin means no cancer cells are seen at the edge of the tissue, suggesting the tumour was removed entirely.

  • A positive margin means cancer cells are found at the cut edge, suggesting that some tumour may remain.

Sometimes the distance between the tumour and the closest margin is measured, even when margins are negative. Margin status is important for planning additional treatment and predicting the risk of local recurrence.

Lymph nodes

Lymph nodes are small immune organs that filter lymph fluid and trap abnormal cells, including cancer cells. Medullary thyroid carcinoma commonly spreads to lymph nodes in the neck and upper chest.

During surgery, lymph nodes from around the thyroid and neck may be removed in procedures such as central neck dissection (levels 6 and 7) and lateral neck dissection (levels 1 through 5).

The pathologist examines each lymph node under the microscope and reports:

  • The number of lymph nodes examined.

  • How many contained cancer cells (positive nodes).

  • The size of the largest tumour deposit.

  • Whether extranodal extension is present, meaning tumour cells have grown through the lymph node capsule into surrounding tissue.

Lymph node involvement determines the nodal stage (pN) and helps estimate the risk of cancer spreading to other parts of the body. It also helps guide decisions about additional treatment, such as systemic therapy or radiation.

Biomarkers for medullary thyroid carcinoma

Biomarkers are measurable features that provide important information about how a tumour behaves, the likelihood of hereditary disease, and whether specific treatments may be effective. Biomarker testing for medullary thyroid carcinoma may involve examining blood samples, tumour tissue, or genetic material (DNA).

Biomarkers for medullary thyroid carcinoma are usually assessed using one or more of the following types of tests:

  • Germline genetic testing: A blood test that looks for inherited changes in genes such as RET. These results can confirm the presence of a hereditary disease and identify family members at risk.

  • Somatic tumour testing: A test performed on the tumour itself to look for mutations or fusions acquired by cancer cells. This may use polymerase chain reaction (PCR), next-generation sequencing (NGS), or fluorescence in situ hybridization (FISH).

  • Immunohistochemistry (IHC): A test performed on tumour tissue using antibodies to identify specific proteins produced by tumour cells.

  • Serum biomarkers: Blood tests that measure calcitonin and CEA levels can help diagnose medullary thyroid carcinoma and monitor the response after treatment.

Different tests provide different types of information, and their results may be reported in various ways. Genetic test results may be described as positive (a mutation is present), negative, or variant of uncertain significance (a genetic change is found, but its importance is unclear). Tumour tissue testing may report the specific gene affected, the type of mutation, and whether targeted treatment may be helpful. IHC results are described as positive or negative depending on whether the tumour cells produce the protein being tested.

RET mutations

Mutations in the RET proto-oncogene are the most common biomarker in medullary thyroid carcinoma. RET testing may be performed on a blood sample to look for inherited (germline) mutations or on tumour tissue to identify acquired (somatic) mutations.

RET results may include:

  • The specific mutation was identified.

  • Whether the mutation is inherited or tumour-specific.

  • The associated MEN2 syndrome risk level.

  • Whether targeted therapies that inhibit RET may be effective.

RAS mutations

RAS mutations are most commonly identified through tumour-based molecular testing such as NGS. These mutations are usually somatic (acquired rather than inherited).

RAS-mutated tumours often behave less aggressively than RET-mutated tumours, but all medullary thyroid carcinomas require careful follow-up. RAS results are usually reported by listing the affected gene (HRAS, KRAS, or NRAS) and the specific mutation.

Gene fusions

Gene fusions are rare in medullary thyroid carcinoma but may be identified when broad molecular testing (such as NGS with fusion panels) is performed. A gene fusion result identifies the two genes involved and confirms that tumour cells are producing an abnormal fused protein that may contribute to cancer growth. Some fusions may have implications for targeted therapy, depending on the genes involved.

Pathologic stage (pTNM)

The pathologic stage for medullary thyroid carcinoma is based on the TNM staging system developed 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). Generally, a higher number corresponds to 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 tumour size and whether cancer cells have extended beyond the thyroid.

  • T1 – The tumour is 2 cm or smaller and contained within the thyroid gland.

  • T2 – The tumour is greater than 2 cm but 4 cm or smaller and still contained within the thyroid gland.

  • T3 – The tumour is larger than 4 cm, or cancer cells extend into the muscles just outside the thyroid gland.

  • T4 – Cancer cells extend to structures or organs outside the thyroid gland, including the trachea, larynx, esophagus, or major blood vessels.

Nodal stage (pN)

The nodal stage depends on whether cancer cells are found in lymph nodes and the location of those nodes.

  • N0 – No cancer cells are found in any lymph nodes examined.

  • N1a – Cancer cells are found in one or more lymph nodes in the central compartment of the neck (levels 6 or 7).

  • N1b – Cancer cells are found in one or more lymph nodes in the lateral neck (levels 1 through 5).

  • NX – No lymph nodes were submitted for examination.

The pT and pN stages, together with information about distant metastasis (M stage), determine the overall stage and guide treatment decisions.

What happens after the diagnosis?

After a diagnosis of medullary thyroid carcinoma is made, your healthcare team will review your pathology report, imaging results, blood tests (including calcitonin and CEA levels), and genetic testing to outline a treatment plan. The team often includes an endocrinologist, surgeon, medical oncologist, radiation oncologist, and genetic counsellor.

Treatment typically involves surgical removal of the thyroid gland (total thyroidectomy), often combined with removal of lymph nodes in the neck if there is a high risk of spread. For hereditary cases, surgery may be recommended at an early age to prevent cancer from developing.

Targeted therapies that inhibit RET or other altered pathways may be recommended for advanced, recurrent, or metastatic disease, especially when specific mutations are identified. Chemotherapy and radiation play a more limited role but may be used in select cases.

After treatment, you will need regular follow-up with blood tests to monitor calcitonin and CEA levels, which help detect persistent or recurrent disease. Imaging studies may also be performed if tumour markers rise or new symptoms appear. Family members may be offered genetic testing if hereditary medullary thyroid carcinoma is suspected.

Questions to ask your doctor

  • What was the histologic grade of my tumour (low grade or high grade), and how does that affect my prognosis?

  • What was the size of the tumour, and did it show extrathyroidal extension?

  • Did the tumour show vascular invasion or lymphatic invasion?

  • Were the surgical margins negative, and was all of the tumour removed?

  • Were lymph nodes involved, and if so, how many, and were there signs of extranodal extension?

  • What is my pathologic stage (pT and pN categories)?

  • What treatments do you recommend next, and what are the potential side effects?

  • Should my family members be tested for hereditary syndromes such as MEN2 or FMTC?

Other helpful resources

American Thyroid Association (ATA)
American Cancer Society
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