Medullary Thyroid Carcinoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 21, 2026

Medullary thyroid carcinoma is a rare type of thyroid cancer that starts from C cells (also called parafollicular cells). The thyroid is a butterfly-shaped gland at the front of the neck. Most thyroid cancers begin in follicular cells, which make thyroid hormone. Medullary thyroid carcinoma differs because it arises from C cells, which produce a hormone called calcitonin that helps regulate blood calcium levels.

Medullary thyroid carcinoma accounts for only about 1 to 2 percent of all thyroid cancers. It can appear as a single nodule in the thyroid or as multiple nodules, sometimes involving both lobes of the gland.

What are the symptoms of medullary thyroid carcinoma?

Symptoms depend on the size of the tumor and whether it has spread beyond the thyroid. Many people first notice a lump in the neck. Other symptoms may include:

Swelling in the neck.
Difficulty swallowing.
Hoarseness or other changes in the voice.
A persistent cough that is not related to a cold.

Because medullary thyroid carcinoma produces calcitonin, and sometimes other hormone-like substances, some patients also develop diarrhea or flushing of the face, particularly when the tumor is advanced, and hormone levels in the blood are very high. Other patients have no symptoms at all, and the tumor is found by chance on imaging or blood tests performed for other reasons.

What causes medullary thyroid carcinoma?

Medullary thyroid carcinoma can occur in two main settings: sporadic (not inherited) and hereditary (inherited).

Sporadic medullary thyroid carcinoma. About 75 to 80 percent of cases are sporadic, meaning they occur by chance. Sporadic tumors usually appear as a single nodule in the thyroid and are more common in adults without any family history of the disease.
Hereditary medullary thyroid carcinoma. The remaining 20 to 25 percent of cases are caused by an inherited change in a gene that is passed down from parent to child. People with hereditary medullary thyroid carcinoma tend to develop the cancer at a younger age and often have tumors in both lobes of the thyroid.

Almost all hereditary cases and many sporadic cases are caused by changes in a gene called RET. Because the hereditary forms have important implications for family members, every patient diagnosed with medullary thyroid carcinoma should be referred for genetic counseling and testing, regardless of family history.

Genetic syndromes associated with medullary thyroid carcinoma

Inherited changes in the RET gene cause a group of conditions called multiple endocrine neoplasia type 2 (MEN2). People with MEN2 are at high risk of developing medullary thyroid carcinoma, often at a young age, as well as other tumors.

Multiple endocrine neoplasia type 2A (MEN2A). The most common form. People with MEN2A are at high risk of medullary thyroid carcinoma, pheochromocytoma (a tumor of the adrenal gland that can cause spells of high blood pressure), and parathyroid adenoma (a small tumor of the parathyroid glands that can cause high calcium levels in the blood).
Multiple endocrine neoplasia type 2B (MEN2B). A less common but more aggressive form. In addition to medullary thyroid carcinoma and pheochromocytoma, people with MEN2B often have distinctive physical features, such as small bumps on the lips and tongue (mucosal neuromas) and a tall, slim build with long arms and legs (marfanoid habitus).
Familial medullary thyroid carcinoma (FMTC). A variant of MEN2A in which medullary thyroid carcinoma occurs in multiple family members, but the other endocrine tumors seen in MEN2A are not present.

Identifying a hereditary cause has important implications for both the patient and their family. Children and other first-degree relatives (parents, siblings) who carry the inherited RET mutation can undergo preventive removal of the thyroid gland (preventive thyroidectomy) before cancer develops, which is highly effective at preventing medullary thyroid carcinoma entirely. The specific RET mutation found determines both the recommended age for preventive surgery and the risk of the other tumors associated with MEN2.

How is the diagnosis of medullary thyroid carcinoma made?

The diagnosis usually begins when a thyroid nodule is found during a physical exam or on an imaging test such as an ultrasound, CT scan, or MRI. Blood tests often show elevated levels of calcitonin and carcinoembryonic antigen (CEA), both of which are characteristically increased in medullary thyroid carcinoma. A fine needle aspiration (FNA) biopsy is usually performed next, in which a thin needle is used to remove a small sample of cells from the nodule for examination under the microscope. Measuring calcitonin in the fluid washed through the needle can be especially helpful in suggesting the diagnosis. Under the microscope, medullary thyroid carcinoma has a distinctive neuroendocrine appearance (described in the next section). Immunohistochemistry is a laboratory test that uses antibodies to detect specific proteins in the tumor cells; in medullary thyroid carcinoma, the tumor cells typically stain positive for calcitonin (confirming C-cell origin), TTF-1, synaptophysin, and chromogranin (markers of neuroendocrine cells), and are negative for thyroglobulin and PAX8 (which distinguishes them from papillary and follicular thyroid carcinomas). Imaging is also used to check for spread to lymph nodes in the neck and chest and to distant parts of the body such as the liver, lungs, or bones. Because the finding of medullary thyroid carcinoma has implications for family members, RET genetic testing is typically arranged at the time of diagnosis (see Biomarkers below).

What does medullary thyroid carcinoma look like under the microscope?

Medullary thyroid carcinoma is a neuroendocrine tumor, meaning the tumor cells share features with both hormone-secreting cells and nerve cells. Under the microscope, the tumor typically shows:

Nests, cords, or sheets of uniform tumor cells. Unlike most other thyroid cancers, the cells do not form follicles (small round structures) or papillae (finger-like projections).
Round or spindle-shaped cells with “salt-and-pepper” nuclei. This speckled appearance of the genetic material inside the nucleus is a classic feature of neuroendocrine tumors.
Amyloid deposits. Many medullary thyroid carcinomas contain pink, waxy-looking material called amyloid, which is formed from abnormal calcitonin. When present, amyloid strongly supports the diagnosis.

In some tumors, the cells may look more aggressive: they may divide more rapidly, show areas of tumor cell death (necrosis), or have a more irregular appearance. These features are used to assign the tumor a histologic grade (described below).

Histologic grade

Histologic grade describes how aggressive the tumor appears under the microscope. It is based on how quickly the tumor cells are dividing (as measured by the mitotic count and Ki-67 proliferation index) and on whether areas of tumor cell death (necrosis) are present. There are two grades for medullary thyroid carcinoma:

Low grade. Fewer than 5 mitotic figures per 2 square millimeters of tissue, a Ki-67 proliferation index below 5 percent, and no tumor necrosis.
High grade. At least one of the following: 5 or more mitotic figures per 2 square millimeters, a Ki-67 proliferation index of 5 percent or more, or the presence of tumor necrosis.

High grade medullary thyroid carcinomas are more likely to spread and are associated with worse outcomes, so histologic grade is an important part of the pathology report.

Biomarkers in medullary thyroid carcinoma

Biomarker testing is central to the management of medullary thyroid carcinoma. It identifies patients with hereditary diseases (so family members can be tested and, if needed, undergo preventive surgery) and those who may benefit from targeted drug therapy. Testing is typically performed on both the tumor tissue and a blood sample.

RET mutations

The RET gene makes a receptor protein involved in cell growth. A mutation in this gene keeps the protein switched on all the time, driving tumor growth. RET testing is the single most important biomarker test in medullary thyroid carcinoma and is typically performed on both the tumor and a blood sample:

Germline RET mutation (found in the blood) means the mutation was inherited and is present in every cell in the body. About 25 percent of medullary thyroid carcinomas are caused by germline RET mutations. A germline mutation can be passed on to children, and all first-degree relatives (parents, siblings, children) should be offered genetic testing. Carriers can undergo preventive removal of the thyroid gland before cancer develops.
Somatic RET mutation (found only in the tumor) means the mutation arose in the cancer cells during the person’s lifetime and is not inherited. About 40-50% of sporadic medullary thyroid carcinomas harbor a somatic RET mutation. These mutations do not affect family members.

Because the distinction between germline and somatic has such important implications for family members, standard practice is to perform both tumor and blood-based RET testing for every patient with medullary thyroid carcinoma, even when there is no family history of the disease.

The specific RET mutation identified also matters. Different mutations carry different risks of aggressive disease and different associated features. For example, a mutation at a position called codon 918 (most common in MEN2B) is associated with the most aggressive disease and the earliest recommended age for preventive surgery. Mutations at codon 634 (most common in MEN2A) are associated with a higher risk of pheochromocytoma and parathyroid tumors.

In advanced or metastatic medullary thyroid carcinoma, RET-targeted drugs such as selpercatinib and pralsetinib are highly effective and have transformed treatment for patients with RET-mutant disease. For a more detailed discussion, see our dedicated article on RET mutations and fusions in thyroid cancer.

RAS mutations

The RAS family of genes (HRAS, KRAS, and NRAS) makes proteins that help control cell growth. RAS mutations are found in a small subset of sporadic medullary thyroid carcinomas without a RET mutation. These mutations are almost always somatic (not inherited) and tend to be associated with somewhat less aggressive behavior than RET-mutant tumors. There is currently no standard RAS-targeted therapy for medullary thyroid carcinoma.

Serum calcitonin and CEA

Calcitonin and CEA are proteins produced by medullary thyroid carcinoma cells and released into the bloodstream. Blood levels are usually high at the time of diagnosis and are used in three ways: to support the initial diagnosis, to monitor whether the tumor has been completely removed after surgery (levels should fall dramatically), and to watch for recurrence during long-term follow-up. A rising calcitonin or CEA level after surgery is often the first sign that the cancer has come back.

Tumor size

After the tumor is removed, it is measured in three dimensions, and the largest measurement is reported. Tumor size is important because it is used to determine the pathologic tumor stage (pT), and larger tumors are more likely to have spread to lymph nodes or distant parts of the body.

Extrathyroidal extension

Extrathyroidal extension means that the cancer has grown beyond the thyroid gland into the surrounding tissues. Pathologists describe two types:

Microscopic extrathyroidal extension. Small amounts of tumor just beyond the thyroid that can only be seen under the microscope.
Gross (macroscopic) extrathyroidal extension. Tumor growth visible during surgery or on imaging, extending into nearby structures such as the neck muscles, voice box (larynx), windpipe (trachea), food pipe (esophagus), or major blood vessels.

Gross extrathyroidal extension raises the tumor stage and is associated with a higher risk of recurrence.

Vascular invasion

Vascular invasion means that tumor cells have entered blood vessels in or around the tumor. Once inside a blood vessel, tumor cells can travel to distant parts of the body such as the liver, lungs, or bones. Vascular invasion is important in medullary thyroid carcinoma because it increases the risk of distant spread and may prompt more intensive monitoring after treatment.

Lymphatic invasion

Lymphatic invasion means that tumor cells have entered lymphatic channels, the tiny vessels that carry a fluid called lymph toward lymph nodes. From there, tumor cells can spread to lymph nodes in the neck and upper chest. Medullary thyroid carcinoma commonly spreads to lymph nodes, and lymphatic invasion is an important finding.

Margins

A margin is the edge of the tissue removed during surgery. The pathologist examines the margins to see whether any cancer cells reach the cut edge.

Negative margin. No cancer cells are seen at the edge. This suggests that the tumor was completely removed.
Positive margin. Cancer cells are seen at the edge, meaning some tumor may remain. Additional treatment may be recommended.

Lymph nodes

Lymph nodes are small immune organs that filter lymph fluid. Cancer cells can travel from the thyroid through lymphatic channels to nearby lymph nodes. Medullary thyroid carcinoma spreads to lymph nodes more often than most other thyroid cancers, so removing and examining lymph nodes is a standard part of surgery.

Neck dissection

A neck dissection is a surgical procedure in which lymph nodes are removed from specific regions of the neck. The central compartment (level 6), just around the thyroid, is almost always explored in medullary thyroid carcinoma. When cancer is known or suspected in the lateral neck (levels 1 through 5), a more extensive dissection is performed. Lymph nodes on the same side of the neck as the tumor are called ipsilateral (same side), while those on the opposite side are called contralateral (opposite side).

How lymph nodes are described in the report

If lymph nodes are removed, the pathologist will report:

The total number of lymph nodes examined.
The number of lymph nodes that contain cancer cells. These are called positive nodes.
The size of the largest deposit of cancer cells within a lymph node.
Whether extranodal extension is present. This means cancer cells have grown beyond the outer edge (capsule) of the lymph node into the surrounding tissue.

Pathologic stage (pTNM)

The pathologic stage for medullary thyroid carcinoma is based on the size and extent of the tumor (pT), whether cancer is found in nearby lymph nodes (pN), and whether the cancer has spread to distant parts of the body (pM). Most pathology reports include details for pT and pN.

Tumor stage (pT)

T1: Tumor 2 cm or smaller and still within the thyroid.
- T1a: Tumor 1 cm or smaller.
- T1b: Tumor larger than 1 cm but not larger than 2 cm.
T2: Tumor larger than 2 cm but not larger than 4 cm and still within the thyroid.
T3: Tumor larger than 4 cm, or with early growth into the muscles around the thyroid.
- T3a: Tumor larger than 4 cm but still within the thyroid.
- T3b: Tumor of any size with gross extrathyroidal extension into the strap muscles (the muscles just in front of the thyroid).
T4: Tumor with more extensive growth outside the thyroid.
- T4a: Tumor growing into the soft tissues under the skin, voice box (larynx), windpipe (trachea), food pipe (esophagus), or nearby nerves.
- T4b: Tumor growing into the tissue at the front of the spine or surrounding major blood vessels in the neck or chest.

Nodal stage (pN)

NX: No lymph nodes were submitted for examination.
N0: No cancer was found in any of the lymph nodes examined.
N1: Cancer was found in one or more lymph nodes.
- N1a: Cancer in lymph nodes in the central part of the neck (level 6) or upper chest (level 7).
- N1b: Cancer in lymph nodes on the side of the neck (levels 1 through 5).

What happens after the diagnosis?

After the diagnosis has been confirmed, your healthcare team will review your pathology report, imaging studies, blood tests (including calcitonin and CEA levels), and genetic test results to plan treatment. This team typically includes an endocrinologist, a thyroid surgeon, a medical oncologist, and — importantly for medullary thyroid carcinoma — a genetic counselor.

The main treatment is surgery to remove the entire thyroid gland (total thyroidectomy), usually combined with removal of lymph nodes in the central neck and, when appropriate, the lateral neck. Unlike most other thyroid cancers, medullary thyroid carcinoma does not take up radioactive iodine, so radioactive iodine therapy is not used. External beam radiation may be used in selected cases when surgery cannot completely remove the tumor or when there is a high risk of local recurrence.

For patients with advanced, recurrent, or metastatic disease, RET-targeted drugs (selpercatinib or pralsetinib) are highly effective when a RET mutation is present and have largely replaced older therapies. Before these targeted drugs were available, treatment options for advanced medullary thyroid carcinoma were much more limited.

After treatment, long-term follow-up is essential and includes regular measurement of calcitonin and CEA in the blood, clinical examination, and imaging when needed. A slow or stable rise in these markers may be monitored, while a rapid rise often prompts further imaging and sometimes a change in treatment.

For patients with a germline RET mutation, family members should be offered genetic testing. Children who carry the mutation can be monitored with blood tests and may undergo preventive thyroidectomy at an age determined by the specific mutation — in some high-risk cases, as early as the first year of life. This preventive approach is highly effective and can prevent medullary thyroid carcinoma from ever developing.

Questions to ask your doctor

Has RET genetic testing been performed on both my tumor and a blood sample?
Was a germline (inherited) RET mutation identified? If so, what is the specific mutation, and what does it mean for my family?
Have my family members been referred for genetic counseling and testing?
What was the histologic grade of my tumor (low grade or high grade)?
How large was the tumor, and did it grow beyond the thyroid?
Was vascular or lymphatic invasion present?
Were the surgical margins negative?
How many lymph nodes were involved, and was extranodal extension present?
What is my pathologic stage (pT and pN)?
What are my calcitonin and CEA levels now, and how often will they be rechecked?
If my cancer comes back or spreads, am I a candidate for targeted therapy (such as selpercatinib or pralsetinib)?