Thyroid Cancer

In most cases, the specific causes of thyroid cancer are not known. However, there are risk factors associated with age, gender, genetics, and radiation exposure:

• Gender – women are two to three times more likely than men to develop thyroid cancer.
• Age – two-thirds of thyroid cancers are diagnosed in people between the age of 20 and 55.
• Exposure to high doses of radiation – x-rays received during the course of routine medical care are not a risk for thyroid cancer. Exposures that may increase risk include childhood x-ray treatments that were practiced before the 1960s, x-ray treatment of breast cancer or Hodgkin disease, or exposure to nuclear disasters.
• Family history – having a family history of medullary thyroid cancer, multiple endocrine neoplasia (MEN), goiters, or precancerous colon polyps increases the risk of developing thyroid cancer.
• Genetics – for example, some cases of medullary thyroid cancer (MTC) are caused by a mutation in the RET gene. Individuals with this gene have a high risk of developing thyroid cancer. If you have a family history of MTC or multiple endocrine neoplasia (MEN), blood tests are available to look for the mutation.

A number of conditions can cause symptoms similar to thyroid cancer. For example, thyroid nodules or lumps are common and usually not cancerous.

However, there are currently no screening tests for early detection of thyroid cancer. That means detection relies on you or your healthcare practitioner recognizing the signs and symptoms of thyroid cancer. 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 for thyroid cancer testing are to aid in diagnosis, staging, assessing treatment options, and monitoring treatment.

Laboratory tests

Screening
Screening tests are not recommended for people who have no symptoms of thyroid cancer and have an average risk for developing thyroid cancer.

However, very high-risk individuals who have a family history of medullary thyroid cancer (MTC), or multiple endocrine neoplasia (MEN 2), may wish to undergo a blood test to screen for RET gene mutations associated with developing 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 to rule out other conditions. Laboratory tests help your healthcare provider diagnose your signs and symptoms, assess thyroid function, and determine the type of thyroid cancer.

Blood tests 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.
• T3 and Free T4 (thyroid hormones)—these are hormones made by the thyroid gland. They are sometimes measured along with TSH to evaluate thyroid function. Levels are usually normal with thyroid cancer.
• 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.
• RET oncogene—if your healthcare practitioner suspects that you have MTC, or if you have a family history of MTC, your DNA may be tested for a mutation of the RET gene. This test is now considered the mainstay for diagnosing MTC.
• Carcinoembryonic antigen (CEA)—blood tests for this protein are sometimes used to look for MTC. The antigen is often elevated in people with MTC.

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. Patients usually return to home or work shortly after the biopsy with a small dressing (bandaid) over the area. A pathologist will examine the cells under a microscope. (For in-depth information, see the article on Anatomic Pathology.)

Molecular testing of biopsied tissue—up to 30% of thyroid biopsies are “indeterminate,” meaning it is not clear if they are cancerous. Diagnosing those cases often requires surgical removal of all or part of the thyroid. To avoid unnecessary surgeries, scientists have developed molecular tests to help determine if nodules are malignant or benign. While molecular analyses show promise for aiding in diagnosis, these tests need more evaluation before they are widely adopted:

• Somatic mutation testing—indeterminate results from the examination of biopsied thyroid tissue may be resolved by testing the tissue for genetic mutations that are present in cancerous thyroid cells. Those mutations include: RAS, RET/PTC, PAX8–PPAR-γ, and BRAF V600E. BRAF can also be tested to evaluate the risk of papillary thyroid cancer reoccurring.
• 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 blood stream, they also offer promise for diagnostic blood tests.

Guide and Monitor Treatment

• Thyroglobulin (Tg)—this is a blood test for a protein made by the thyroid. Thyroglobulin levels may be tested before, during, and after treatment of papillary and follicular cancers. If the thyroid was surgically removed, these levels should be very low after treatment. If the levels is high, or rises after treatment, 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 immune proteins produced 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 the blood of the person tested. If the antibodies are present, either the Tg test cannot be used to monitor levels or a method that is not affected by TgAb 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 genes and proteins that those treatments target. For people with MTC, that includes the RET oncogene. Individuals with advanced papillary and follicular thyroid cancer may also be tested for genes that suggest they will benefit from targeted therapy.

Non-laboratory tests

• Radioactive iodine uptake—this test can assist in the evaluation of a thyroid nodule. It is also used to look for recurrence in patients who have had previous surgery for papillary or follicular thyroid cancer and have an increasing thyroglobulin level. It takes advantage of how iodine is an important component of thyroid hormones. During the test, a small amount of radioactive iodine is swallowed or injected; pictures are taken at timed intervals to track the radioactive iodine's location. Before surgery, nodules that take up radioactive iodine are usually not cancerous. Nodules that fail to take up radioactivity may or may not be cancerous and would require further evaluation, such as a fine needle aspiration biopsy (FNA). 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.
• Ultrasound—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.
• Other imaging tests—computed tomography (CT) scans, positron emission tomography (PET) scans, or magnetic resonance imaging (MRI) may be used in certain cases to determine the tumor's spread, or when there is no ultrasound available. 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, higher stages denote more spread of the cancer. A 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 a person's age and the type of thyroid cancer they have.

For papillary and follicular thyroid cancer in people younger than 45:

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.

For papillary and follicular thyroid cancer in people older than 45:

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 0: Cancer is only detected with screening; no tumor is found in the thyroid.

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 to the neck. The cancer may have spread to lymph nodes or to distant parts of the body, such as the lungs and bones.

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. Individuals treated with surgery will also require hormone therapy to replace those normally made by the thyroid.

Besides surgery, treatments for thyroid cancer include:

• Radioactive iodine therapy
• 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 so-called 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.

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