Medullary Thyroid Cancer

Medullary thyroid cancer is a rare form of thyroid cancer that develops in special cells inside the thyroid gland. While it accounts for only a small percentage of thyroid cancers, understanding this condition is important because it behaves differently from other thyroid cancers and may run in families.

Table of contents

• What is medullary thyroid cancer?
• Affected body part
• How common is this cancer?
• Causes and genetic factors
• Signs and symptoms
• How is it diagnosed?
• Treatment options
• Outlook and prognosis

What is medullary thyroid cancer?

Medullary thyroid cancer (MTC) is a type of cancer that forms inside your thyroid gland^[1]. Unlike the more common types of thyroid cancer, MTC develops from special cells called parafollicular C cells (also known as C cells). These cells are located in the inner part of the thyroid, which is called the medulla^[2].

The C cells have a specific job in your body. They make a hormone called calcitonin, which helps control calcium levels in your blood and has a weak effect on bone growth^[6]. When medullary thyroid cancer develops, these C cells grow out of control^[1].

MTC is different from other thyroid cancers because it does not make thyroid hormone. This means it behaves differently and requires different treatment approaches than cancers that develop from the cells that make thyroid hormone^[6].

• Thyroid gland (specifically the medulla)
• Parafollicular C cells
• Lymph nodes (can spread here)

How common is this cancer?

Medullary thyroid cancer is rare. While thyroid cancer in general is fairly common, MTC makes up only a small portion of cases. In the United States, approximately 4% to 10% of all thyroid cancers are medullary thyroid cancer^[1]. About 1,000 people receive an MTC diagnosis each year in the U.S.^[1].

In Korea, medullary thyroid cancer accounts for 0.6% of all thyroid cancers, though the incidence has increased steadily between 1997 and 2011^[4].

Causes and genetic factors

About 75% of medullary thyroid cancer cases (3 in 4) are sporadic. This means the cancer happens in people who don’t have a family history of the disease^[1]. Scientists haven’t yet figured out the exact cause of sporadic MTC. However, 40% to 50% of people with sporadic MTC have changes (mutations) in a gene called the RET gene that they develop later in life rather than being born with^[1].

In up to 25% of cases (1 in 4), MTC is due to an inherited condition called multiple endocrine neoplasia type 2 (MEN2)^[1]. This inherited form means the disease can run in families. There are different subtypes of MEN2:

• MEN2A: People with MEN2A have a high chance (90%) of getting MTC. They may also develop tumors of the adrenal glands called pheochromocytomas or tumors in the parathyroid glands^[1].
• MEN2B: Some cases of MEN2B are inherited, but most of the time they are not. People with MEN2B have a 100% chance of getting MTC at a very young age. They may also develop pheochromocytomas and growths called neuromas in the lining of the mouth or digestive tract^[1].
• Familial medullary thyroid cancer (FMTC): People with FMTC have a RET gene mutation but only develop MTC, not other tumors^[1].

If you have the RET gene mutation, you may be able to get preventive surgery to remove your thyroid gland before cancer develops^[1].

The biggest risk factor for medullary thyroid cancer is a family history of MTC or MEN syndrome. Up to 20% of patients with medullary thyroid cancer will have a genetic problem^[17]. Significant radiation exposure to the head, neck, or chest is another risk factor, though MTC is less likely than other thyroid cancers to be caused by radiation therapy^[8].

Signs and symptoms

In many cases, people have MTC for a long time before they notice symptoms because the tumor remains small^[1]. When symptoms do appear, they typically include:

• A painless lump (nodule) on the upper part of your thyroid gland in the front of your neck. Between 75% and 95% of people have this at diagnosis^[1].
• Swollen lymph nodes in your neck. About 70% of people have this at diagnosis^[1].

In rare cases, an enlarged thyroid nodule can cause:

• Hoarseness or changes in voice
• Difficulty swallowing
• Breathing issues or shortness of breath
• A cough, sometimes producing blood
• Pain in the neck, jaw, or ear^[3]

In advanced stages of MTC, high levels of calcitonin produced by the tumor can cause diarrhea and flushing of the skin^[3].

How is it diagnosed?

Medullary thyroid cancer usually presents as a lump or nodule on your thyroid gland. You may notice it yourself, or your healthcare provider may discover it during a routine neck exam. Sometimes, providers discover it accidentally with imaging tests you get for other reasons^[1].

Your provider will likely recommend the following tests to help diagnose MTC:

Imaging tests: These can help identify the nodule on your thyroid. Tests might include thyroid ultrasound, a CT scan, or MRI^[1].

Fine needle aspiration (needle biopsy): Your provider will take a small tissue sample from the nodule on your thyroid using a very thin needle. A specialist called a pathologist will examine these cells under a microscope to check for cancer^[1].

Blood tests: These may include tests that measure your levels of calcitonin and carcinoembryonic antigen (CEA). These levels are typically elevated in people with MTC^[1]. Your provider will also check your thyroid hormone levels^[1].

Genetic testing: If you’re diagnosed with MTC, your provider may recommend genetic testing to check for mutations in the RET gene. This is crucial for identifying whether you have an inherited form of MTC and can help guide treatment decisions. Even without a family history, patients with medullary thyroid cancer should be evaluated for a genetic cause since they may be the first in the family to be diagnosed^[17].

Treatment options

The primary treatment for medullary thyroid cancer is surgery. Unlike other types of thyroid cancer, MTC does not respond to radioactive iodine therapy, so complete removal of the cancer during the first operation gives the best chance of cure^[17].

Surgery

Total thyroidectomy is the removal of the entire thyroid gland. This is usually the first type of surgery performed for MTC^[1].

Neck dissection removes lymph nodes from the neck. The surgeon may also remove other tissues around the thyroid. This is often done at the same time as the total thyroidectomy if the doctor thinks there is cancer in the lymph nodes^[14].

If you have MEN syndrome, your doctor will need to check for and possibly treat other tumors, especially pheochromocytoma, before thyroid surgery^[17].

Hormone therapy

After surgery to remove all of the thyroid, you will need to take a medicine called levothyroxine to replace the thyroid hormone your body needs. This is given as a pill once a day, and you will need to take it for the rest of your life^[14].

Radiation therapy

Radiation therapy is not commonly used to treat medullary thyroid cancer, but external radiation therapy may be offered after surgery for advanced cancers. It may also be used to treat MTC that has spread to many nearby tissues or that couldn’t be completely removed with surgery^[14].

Targeted therapy

For advanced or metastatic medullary thyroid cancer, targeted therapy drugs may be used. These medicines work by targeting specific molecules in cancer cells to stop their growth. Targeted therapy drugs that may be used include:

• Vandetanib and cabozantinib are multi-kinase inhibitors that can prolong disease progression-free survival^[15].
• Selpercatinib and pralsetinib are newer, more selective RET inhibitors that have shown promising results in recent clinical trials. Selpercatinib is approved for adults and children aged 2 years or older with advanced or metastatic RET-mutant MTC who require systemic therapy^[11].

Chemotherapy

Chemotherapy is generally used only if other treatments haven’t worked or if you cannot participate in clinical trials. Most regimens combine a drug called dacarbazine with other agents^[11].

Outlook and prognosis

MTC usually progresses slowly and is very treatable, especially when caught early^[3]. Most patients with medullary thyroid cancer live at least 5 years after diagnosis. The 10-year survival rate is 65%^[8].

The prognosis depends on several factors, including:

• The stage of cancer at diagnosis
• Whether the cancer has spread to lymph nodes or other parts of the body
• Whether the cancer can be completely removed with surgery
• Your age and overall health

Even when medullary thyroid cancer is more advanced, effective treatment options are available^[6]. After treatment, your doctor will monitor levels of calcitonin and CEA to keep track of how well the treatment is working or if cancer has come back^[2].

If you have a family history of MTC or MEN syndrome, early screening and genetic testing can lead to earlier diagnosis and better outcomes. In some cases, preventive surgery may be recommended for people with certain genetic mutations^[1].