Thyroid Cancer

The exact causes of thyroid cancer are not known. However, it is known that certain changes (mutations) in genes that make up DNA can cause thyroid cells to become cancerous. Although some of these genetic changes may be inherited, most of the changes that cause cancer are acquired during a person’s lifetime. They may happen spontaneously or may be due to something in the environment, such as radiation exposure. Examples of genes that are associated with thyroid cancer include BRAF, KRAS, NRAS, and fusion genes such as RET/PTC, Pax8/PPARG.

There are a number of factors that increase the risk of developing thyroid cancer. Some examples include:

• Gender – women are three times more likely than men to develop thyroid cancer.
• Age – two-thirds of thyroid cancers are diagnosed in people between the ages of 20 and 55.
• Exposure to radiation – x-rays received during the course of routine medical care are not a risk for thyroid cancer. Examples of radiation exposures that may increase risk include:
  • Radiation treatment of certain medical conditions (e.g., breast cancer or Hodgkin disease), and of the head and neck or for some cancers (e.g., lymphoma) during childhood
  • Some childhood low-dose radiation treatments that were practiced before the 1960s
  • Radioactive fallout from nuclear disasters
• Genetics – about 2 out 10 cases of medullary thyroid cancer are caused by an inherited variant in the RET gene. As mentioned above, these cases are called familial medullary thyroid cancer (FMTC) and may be associated with MEN2. Besides FMTC, other types of thyroid cancer can be inherited. Most of these cases are part of familial cancer syndromes such as:
  • Familial adenomatous polyposis
  • Cowden syndrome
  • Carney complex
  • Pendred syndrome
  • Werner syndromePeople who have one of these syndromes are at increased risk of developing thyroid cancer, especially papillary thyroid cancer. There are typically other medical features or family history clues that would make your healthcare provider suspect one of these syndromes.
• Family history – having a close relative, such as a parent, sibling or child with thyroid cancer can increase your risk of developing thyroid cancer, even if it is not associated with a known familial cancer syndrome. In these cases, the genetic basis of the cancer is not clear.

A number of conditions can cause symptoms similar to thyroid cancer. For example, thyroid nodules are abnormal growths of thyroid tissue that form a swelling or lumps within the thyroid gland. These are common and usually not cancerous.

Detection of thyroid cancer relies on you or your healthcare practitioner recognizing the signs and symptoms, since screening tests for thyroid cancer are not recommended in the general population. Palpation of the thyroid is a routine part of a physical exam and may detect abnormalities in the thyroid gland. Talk to your healthcare provider right away if you have any of the following signs and/or symptoms:

• A lump that you can feel on your neck, sometimes with no other symptoms
• Neck swelling
• Voice changes, including increasing hoarseness
• Trouble breathing
• Trouble swallowing
• Swollen neck lymph nodes without an upper respiratory infection

The goals of thyroid cancer testing are to help diagnose and stage the cancer, weigh treatment options, and monitor treatment.

Screening
Screening tests are not recommended if you have no symptoms of thyroid cancer and have an average risk for developing thyroid cancer. However, if you have very high risk because you have a family history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia type 2 (MEN 2), it may be recommended that you are regularly screened with thyroid ultrasounds. In addition, you may receive genetic counseling and genetic testing for RET gene variants associated with MTC.

Diagnosis and Staging
If you have signs or symptoms of thyroid cancer, a healthcare practitioner will feel for changes in your thyroid and lymph nodes and ask about your medical and family history.

Thyroid cancer is ultimately diagnosed by biopsy. However, before a healthcare practitioner decides to perform a biopsy or surgery, you will receive imaging scans and blood tests. These tests help your healthcare provider diagnose your signs and symptoms, assess thyroid function, and, if present, determine the type of thyroid cancer.

Initial testing may include:

• Thyroid-stimulating hormone (TSH)—this is a blood test that evaluates thyroid function. It measures TSH levels released by the pituitary gland. TSH is used to evaluate other conditions that may cause signs and symptoms similar to thyroid cancer. If TSH levels are high, the thyroid may not be making enough hormones, a sign of hypothyroidism. If they are low, it may be a sign of hyperthyroidism. TSH levels are usually normal or high with thyroid cancer.
• Total or free T3 and free T4 (thyroid hormones)—these blood tests measure hormones made by the thyroid gland. These hormones are sometimes measured along with TSH to evaluate thyroid function. Levels are usually normal with thyroid cancer.
• Ultrasound of the thyroid gland—this is also one of the first tests used to evaluate your thyroid. Results of the ultrasound may show suspicious areas or that a nodule is present. It will also show a nodule’s location, size, shape and other characteristics and whether more than one nodule is present. The American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines recommend ultrasound evaluation of thyroid nodules, along with testing TSH levels, to determine if a biopsy is needed.
• Biopsy—a biopsy may be done to examine a small amount of tissue and/or fluid from a thyroid nodule. Often, a fine-needle aspiration (FNA) biopsy is done. This is a procedure that involves inserting a very thin needle into the thyroid nodule and withdrawing cells. An ultrasound may be used to guide the needle into the correct position. A pathologist will examine the cells using a microscope. (For in-depth information, see the article on Anatomic Pathology.)

Additional tests:

• Calcitonin—this is a hormone produced by special cells in the thyroid called C-cells. It plays a role in how the body uses calcium. The cells that make calcitonin can also develop into medullary thyroid cancer. This test may be used during diagnosis to check for MTC. Elevated levels indicate that MTC is likely present.
• Carcinoembryonic antigen (CEA)—this is a protein that may be elevated with certain types of cancer. Blood tests for this protein are sometimes used to look for MTC. The protein is often elevated in people with MTC.
• Molecular testing of biopsied tissue—up to 30% of thyroid biopsy results are “indeterminate,” meaning it is not clear if they are cancerous. Diagnosing those cases often requires removing all or part of the thyroid during surgery. To avoid unnecessary surgeries, molecular tests may be used to help determine if nodules are cancerous or benign. Testing may include:
  • Molecular testing of the biopsy material to detect cancer-causing variants (mutations) in certain genes (e.g., BRAF, KRAS, NRAS, and fusion genes such as RET/PTC, Pax8/PPARG).
  • miRNA analysis—miRNAs are small RNA fragments that affect the behavior of certain genes. Since certain miRNAs are linked to cancer development, their presence in biopsied thyroid tissue can help determine if a nodule is malignant. Since miRNAs circulate in the bloodstream, they also offer promise for diagnostic blood tests.

Tests to Guide and Monitor Treatment

• Thyroglobulin (Tg)—this is a blood test for a protein made by the follicular cells of the thyroid. Thyroglobulin levels may be tested once the thyroid has been removed; if no thyroid tissue is left, and there is no remaining thyroid cancer, then thyroglobulin levels should be undetectable. If the level is high, or rises after surgery, it could be a sign that there are still thyroid cancer cells in the body or that the cancer is returning.
• Thyroglobulin antibody (TgAb)—these are proteins produced by the immune system that target thyroglobulin. Depending on the test method used, these antibodies can interfere with the results of the thyroglobulin test if they are present in your blood. If the antibodies are present, either the thyroglobulin test cannot be used to monitor levels or a method that is not affected by thyroglobulin antibodies must be used to monitor levels.
• Calcitonin—in addition to aiding diagnosis of MTC, the blood test for this hormone may be used for monitoring treatment and recurrence of MTC. With successful treatment, calcitonin levels will usually fall to very low levels. If, after successful treatment, calcitonin levels begin to rise, then it is likely that there is a recurrence of medullary thyroid cancer.
• Molecular markers—individuals who may benefit from targeted therapy will receive tests to look for the genetic mutations and proteins that those treatments target. Examples include BRAF mutations or fusion genes such as NTRK or RET/PTC.

Non-laboratory Tests

• Radioactive iodine uptake—this test can assist in the evaluation of a thyroid nodule in patients with low TSH, because it can detect nodules that are producing too much thyroid hormone (which contains iodine). It is also used to look for persistence or recurrence of cancer in patients who have had previous surgery for papillary or follicular thyroid cancer and have an elevated thyroglobulin level. During the test, a small amount of radioactive iodine is swallowed or injected and pictures are taken at timed intervals to track the radioactive iodine’s location. For additional details on this test, visit RadiologyInfo.org. After surgery, areas of increased iodine uptake may represent thyroid cancer, and higher doses of radioactive iodine can be used to treat the cancer.
• Other imaging tests may include chest x-ray, computed tomography (CT) scans, positron emission tomography (PET) scans, or magnetic resonance imaging (MRI). These may be used in certain cases to evaluate the thyroid and/or determine the tumor’s spread to other parts of the body. They may also be used when surgery is planned as part of treatment to remove all or part of the thyroid and in follow up to a surgical procedure.

Thyroid cancer is divided into stages that describe the tumor’s size and how far the tumor has spread through the body. Generally, a higher stage means the tumor is larger and/or the cancer has spread further in the body. Your healthcare practitioner will determine the cancer’s stage primarily through biopsy and imaging tests. Staging is important for determining treatment and prognosis. For more detail, see the section on “Biopsies and examination of tissues” in the Anatomic Pathology feature article.

For thyroid cancer, different staging criteria are used depending on your age and the type of thyroid cancer you have.

Papillary and Follicular thyroid cancer:

Younger people are less likely to die from papillary or follicular thyroid cancer, so the stages for these cancers take this into account.

If you are younger than age 55:

Stage I: The tumor is any size; cancer may be in the thyroid, or may have spread to nearby tissues and lymph nodes. It has not spread to other parts of the body.

Stage II: The tumor is any size; cancer has spread from the thyroid to other parts of the body and may have spread to the lymph nodes.

If you are older than age 55:

Stage I: The tumor is 2 centimeters or smaller; cancer is limited to the thyroid.

Stage II: The tumor is 2-4 centimeters; cancer is limited to the thyroid.

Stage III: The tumor is larger than 4 centimeters and cancer is limited to the thyroid, or the tumor is any size and cancer has spread to just outside the thyroid or has spread to lymph nodes near the trachea or larynx.

Stage IV: The tumor is any size; cancer has spread outside of the thyroid to neck tissues and possibly the lymph nodes, or has spread to distant parts of the body such as lungs and bones.

Medullary thyroid cancer for any age:

Stage I: Tumor is 2 centimeters or smaller; cancer is limited to the thyroid.

Stage II: Tumor is larger than 2 centimeters and cancer is limited to the thyroid or the tumor is any size and cancer has spread just outside the thyroid, but not to lymph nodes.

Stage III: Tumor is any size and cancer has spread to the lymph nodes near the trachea and larynx and may have spread to other neck tissues.

Stage IV: The tumor is any size; cancer has spread beyond the thyroid to other areas such as the trachea, esophagus, and voice box, may have spread to lymph nodes or distant parts of the body such as lungs and bones.

Anaplastic thyroid cancer:

All anaplastic thyroid cancers are considered stage IV because they grow rapidly and are usually not found until they have progressed and spread to other areas of the neck. The cancer may have spread to lymph nodes or to distant parts of the body, such as the lungs and bones.

Since most risk factors for thyroid cancer like age and gender are outside of your control, there is little that can be done to prevent it. However, for individuals who test positive for specific RET variants that increase the risk for developing aggressive MTC, the American Thyroid Association does recommend preventive thyroid removal, even in children.

Most thyroid cancers, especially papillary and follicular cancers, are highly treatable. Thyroid cancer treatment depends on the type of thyroid cancer, how far it has progressed, and your individual health and preferences.

Most thyroid cancers are treated with surgery to remove all or part of the thyroid, followed by one or more therapies to kill or control remaining cancer cells, if needed. Individuals treated with surgery that removes all of the thyroid will also require hormone therapy to replace those normally made by the thyroid.

Besides surgery, treatment options for thyroid cancer include:

• Radioactive iodine therapy (for papillary or follicular cancers)
• External beam radiation therapy (EBRT)
• Chemotherapy
• Targeted therapy

Though surgery and EBRT are still used for some medullary thyroid cancers (MTC), radioactive iodine therapy is not effective against MTC. Researchers have been looking for new drugs that specifically target cancer genes and proteins while avoiding damage to healthy cells. These targeted therapies include the drugs cabozantinib, vandetanib, and sorafenib. These may be used to treat people with large tumors or advanced metastatic cancer.

The targeted therapies sorafenib and lenvatinib have also been used to treat papillary and follicular thyroid cancers that are too advanced for treatment with surgical removal or have become resistant to radioactive iodine therapy.

For additional details on treatment, see the links in the Related Content section.