Thyroid Cancer

Thyroid Cancer

For the past several decades thyroid cancer has been the most common endocrine tumor, with a ~ 5% increase in incidence each year in the USA. Thyroid cancer affects women more often than men and has been increasing over the last decade. Thyroid cancer is commonly first detected as a palpable thyroid gland during a physical exam.

Overall there is estimated to be 56,000 individuals diagnosed with thyroid cancer in the United States each year with only 2,000 dying from their disease. The vast majority of thyroid cancers arise from thyroid follicular cells (93%) and are well-differentiated (DTC). Most of these are categorized on histologic grounds as being papillary thyroid cancers (PTC), or less commonly as follicular thyroid cancers (FTC).1,2,3,4

The thyroid gland produces thyroid hormones, which regulate metabolism, growth, and development. The thyroid gland is located in the front of the neck and is attached to the lower part of the voice box (larynx) and to the upper part of the windpipe (trachea). Thyroid gland tissue envelops the upper trachea and usually four parathyroid glands lie posteriorly. Thyroid cancer is suspected if a small abnormal growth or “nodule” is found protruding from the thyroid gland. Most thyroid nodules are not cancer so diagnostic tests must be performed to determine if the nodule is benign or cancerous.

The main initial diagnostic test of the thyroid is evaluation with an iodine (I 131) scan. If this test shows that the I 131 is not taken up in an area of the gland, the nodule is said to be “cold” and cancer is suspected.  The overall incidence of cancer in a cold nodule is ~15% and is higher in people younger than 40 years of age and those with calcifications.1,2,3,4

Types of Thyroid Cancer

Cancer may arise from different cells of the thyroid gland. By evaluating a sample of the cancer under a microscope, doctors can determine the type of thyroid cancer. There are four main types of thyroid cancer. The thyroid gland may occasionally be the site of other primary tumors, including sarcomas, lymphomas, epidermoid carcinomas, and teratomas. The thyroid may also be the site of metastasis from other cancers, particularly of the lung, breast, and kidney.5,6,7

Papillary: Papillary tumors are the most common form of thyroid cancer, accounting for more than 80% of all cases. Papillary cancers are typically irregular or solid masses that arise from otherwise normal thyroid tissue. More than half of papillary cancers have spread to lymph nodes in the neck. However, papillary cancers rarely spread to distant locations in the body. Papillary cancers typically occur in younger patients (30-50 years) and are commonly associated with a prior exposure to radiation. Patients with papillary cancer are highly curable with currently available treatment techniques.8

Follicular: Follicular cancers account for a smaller percentage of all thyroid cancers (approximately 15%) and rarely occur after radiation exposure. Follicular cancers are more aggressive; they tend to invade blood vessels rather than lymph nodes, and distant spread is therefore more common. Potential sites of distant spread include the lung, bone, brain, liver, bladder, and skin. Patients over 40 have more aggressive disease that is more difficult to treat. Nonetheless, most follicular cancers are very curable.

Medullary: There are two subtypes of medullary thyroid cancer: sporadic and familial. Sporadic almost always occurs on both sides of the thyroid gland. Familial tumors may be malignant or benign and may be associated with a variety of symptoms.

Approximately half of medullary thyroid cancers have spread to lymph nodes. Prognosis depends on the extent of disease at diagnosis—especially spread to lymph nodes—and the ability to completely remove the cancer with surgery.

Anaplastic: Anaplastic thyroid cancer is a rare disease that may also be called undifferentiated cancer. This type of thyroid cancer is very aggressive, grows rapidly, and commonly extends beyond the thyroid gland. It typically occurs in older patients and is characterized by extensive spread in the neck area and rapid progression. Patients typically die of their disease within months of diagnosis.

Well-differentiated tumors are highly treatable and usually curable. Poorly differentiated tumors are less common, aggressive, metastasize early, and have a poorer prognosis.

Signs & Symptoms of Thyroid Cancer

Thyroid cancer is typically detected when an individual or their physician identifies a lump or nodule in the thyroid gland, often during routine physical examination. Additional symptoms or sign attributable to thyroid cancer are uncommon.

Cause

Thyroid cancer begins when healthy cells acquire a genetic change (mutation) that causes them to turn into abnormal cells. Most thyroid cancers develop sporadically, which means for no known reason. Development of thyroid cancer however can occur as a result of radiation exposure and occurs in some hereditary syndromes.

Risk Factors

A risk factor is anything that increases a person’s chance of developing cancer. Risk factors can influence the development of cancer, but most do not directly cause cancer. Many individuals with risk factors will never develop cancer and others with no known risk factors will.

Patients with a history of radiation therapy to the head and neck have an increased risk of cancer and other abnormalities of the thyroid gland.  Cancer of the thyroid gland may appear as early as 5 years after radiation therapy and may appear 20 or more years later. Radiation exposure as a consequence of nuclear fallout has also been associated with a high risk of thyroid cancer, especially in children.

Risk factors for thyroid cancer include the following:

• Radiation exposure.
• Family history of thyroid disease.
• Multiple endocrine neoplasia (MEN) syndrome.
• RET/BRAF gene mutation.
• A history of thyroid goiter.
• Female gender.
• Asian race.

Diagnosis & Tests for Thyroid Cancer

Doctors use many tests to find, or diagnose, cancer. They also do tests to learn if cancer has spread to another part of the body from where it started. A biopsy is the only certain way to confirm a diagnosis of cancer. When performing a biopsy, the doctor takes a sample of tissue for testing in a laboratory. The sample may be removed using a needle and or may be removed during the surgery to treat the nodule. If initial tests indicate that the nodule is cancerous, a surgery will be scheduled to remove as much of the cancer as possible and to determine the extent of spread or the stage of the cancer.1

Fine needle aspiration: Fine needle aspiration is a technique that uses a needle and syringe to withdraw a sample of the cells from a thyroid nodule. The cells can then be evaluated under a microscope to determine if they are cancerous or benign. Since many thyroid nodules are benign, this technique provides a minimally invasive way to determine if surgery is necessary.

Staging
 

When diagnosed with cancer further tests are necessary to determine the extent of spread (stage) of the cancer. Cancer’s stage is a key factor in determining the best treatment. The stage of cancer may be determined at the time of diagnosis or it may be necessary to perform additional tests. In addition to a through history and physical exam, tests used to diagnose, and stage thyroid cancer may include the following:

Ultrasound: Ultrasound uses high frequency sound waves and their echoes to create a two-dimensional image that is projected on a screen. Ultrasound is a simple procedure that may allow doctors to determine if a thyroid nodule is cancerous or benign based on the appearance of the image that is produced. A limitation of ultrasound is that it does not produce a sample of the cells that can be evaluated under a microscope.

About half the people diagnosed with papillary thyroid cancer have lymph node metastases. Neck mapping by ultrasound can be used to evaluate the lymph nodes in the neck for metastatic disease from the jaw down to the clavicle. This is important to ensure that the initial surgery is appropriate for the stage.2,3

Positron emission tomography (PET): Positron emission tomography scanning is an advanced technique for imaging body tissues and organs. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons) that create the production of gamma rays that can be detected by the PET machine to produce a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.

Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body.1

Thyroid Blood Tests:

TSH (thyroid-stimulating hormone) is recommended when a thyroid nodule is present. This hormone is made by the pituitary to regulate the thyroid. TSH tells the thyroid to make hormones that control things like your metabolism. In general, when the TSH is high it usually means that the thyroid levels are low. Likewise, when the TSH is low, it usually means that the thyroid levels are high.

Thyroglobulin is a protein made by the thyroid that can be measured after treatment (surgery) and during follow-up care. If the protein is present, there may still be cancer cells in the body. If it becomes elevated, this could be a sign that the cancer is coming back, and more treatment is needed.

Calcitonin: The C cells in the thyroid make calcitonin. Medullary thyroid cancer starts in the C cells. If you are at risk for medullary thyroid cancer, you may have your calcitonin level checked. It can also be measured after treatment for medullary thyroid cancer. Calcitonin may affect how calcium is made in the body.

Precision Medicine & Personalized Cancer Care

Genetic Mutations

Not all thyroid cancer cells are alike. They may differ from one another based on what genes have mutations that are responsible for the growth of the cancer. Testing is performed to identify genetic mutations or the proteins they produce that drive the growth of the cancer. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.

Researchers are identifying cancer driving genetic mutations responsible for thyroid cancer on an ongoing basis. The following mutations are known to exist in thyroid cancer and precision cancer medicines are either available for use or being developed in clinical trials. Patients should discuss the role of genomic-biomarker testing for the management of their cancer with their treating oncologist.

BRAF: Genetic mutation occurs in ~ 40% of papillary thyroid cancer patients.

MEK: Occurs commonly with BRAF.

MET:

RAS Genes: KRAS and NRAS: RAS is estimated to be present in 20% of papillary and 40% of follicular thyroid cancers.

RET: Occurs in ~ 15% of papillary and can occur in medullary thyroid cancer.

HER2/3: Rare.

PIKC3A: Occurs in 42% of anaplastic and 24% of follicular thyroid cancers.

PTEN Occurs in~ 12% of anaplastic thyroid cancers.

PAX8-PPAR occurs in ~35% of follicular thyroid cancers.

ALK: Rare.

TRK: Rare.

Stages of Thyroid Cancer

Stage I-II: Stage I-II thyroid cancers are generally confined to the thyroid but may include multiple sites of cancer within the thyroid. Thyroid cancer that has spread to nearby lymph nodes is still considered to be in stage I-II when the patient is younger than 45 years of age as the presence of cancer in the lymph nodes does not worsen the prognosis for these younger patients.

Stage III: Stage III thyroid cancer is greater than 4 cm in diameter and is limited to the thyroid or may have minimal spread outside the thyroid. Lymph nodes near the trachea may be affected. Stage III thyroid cancer that has spread to adjacent cervical (neck) tissue or nearby blood vessels has a worse prognosis than cancer confined to the thyroid. However, lymph node metastases do not worsen the prognosis for patients younger than 45 years. Stage III thyroid cancer is also referred to as locally advanced disease.

Stage IV: Stage IV thyroid cancer has spread beyond the thyroid to the soft tissues of the neck, lymph nodes in the neck, or distant locations in the body. The lungs and bone are the most frequent sites of distant spread. Papillary carcinoma more frequently spreads to regional lymph nodes than to distant sites. Follicular carcinoma is more likely to invade blood vessels and spread to distant locations.

Recurrent: Thyroid cancer that has recurred after treatment or progressed with treatment is called recurrent disease.

Treatment & Management of Thyroid Cancer

Treatment for thyroid cancer is tailored to each individual and may include surgery, radiation, and or systemic therapy with precision cancer medicines, immunotherapy or chemotherapy. The specific treatment depends on the type, stage and genomic profile of the cancer.

The standard initial treatment for all thyroid cancers typically includes surgical removal of the thyroid. Radioactive iodine (RAI) is often used in some patients with follicular or papillary cell-derived thyroid cancers. The majority of individuals with follicular or papillary cancer are cured by standard therapy, however a small fraction of follicular and papillary as well as many medullary and almost all anaplastic thyroid cancers are not cured and instead spread to distant metastatic sites.

If grouped together as “advanced thyroid cancers,” aggressive forms of thyroid cancer have a less than 50% 5-year survival rate in contrast to the ~ 98% 5-year survival for papillary and follicular types.

Surgery:  Patients with early stage thyroid cancer are curable with surgical removal of the cancer.  Surgery to remove the entire thyroid is called a total thyroidectomy.  Partial removal of the thyroid is called a lobectomy. The choice of procedure depends on age of the patient and the size of the cancer.

Patients who are at a high risk of cancer recurrence are treated with total thyroidectomy, however a total thyroidectomy is associated with a greater risk of side effects. A total thyroidectomy is a very specialized procedure and is best executed by a skilled surgeon who has performed this operation many times. The thyroid is in close proximity to the voice box and there is a risk of injuring the nerve and thus function of the voice box.

In general surgeons who perform thyroid surgery more frequently have improved outcomes, fewer complications and shorter hospital stays.  Surgeons who perform more than 25 thyroid removal surgeries per year have 55% fewer complications than those who perform less.

Thyroid Hormone Replacement:  Regardless of whether a patient has a lobectomy or has the entire thyroid gland removed, they will receive supplemental thyroid hormone for the rest of their lives. Thyroid hormone is produced by the thyroid gland and is critical for maintaining metabolism. Supplemental thyroid hormone (levothyroxine) serves two purposes: to maintain hormone levels in the absence of a functioning thyroid and to suppress further growth of the gland and thus the cancer. The pituitary gland located in the brain produces a hormone that stimulates the thyroid to grow—called thyroid-stimulating hormone (TSH). In the presence of thyroid hormone, TSH remains low and removes the stimuli to any remaining cancer cells.

Radioactive Iodine Treatment:  Iodine is a natural substance that the thyroid uses to make thyroid hormone. The radioactive form of iodine is collected by the thyroid gland in the same way as non-radioactive iodine. Since the thyroid gland is the only area of the body that uses iodine, the radiation does not concentrate in any other areas of the body. The radioactive iodine that is not taken up by thyroid cells is eliminated from the body, primarily in urine. It is therefore a safe and effective way to test and treat thyroid conditions.

Research indicates that treatment with RAI improves survival for patients with thyroid cancer that has spread to nearby lymph nodes or to distant locations in the body. Anaplastic and medullary thyroid carcinoma are inherently non-sensitive to radioactive iodine treatment.

Radiation Therapy

External beam radiation therapy (EBRT) and Intensity-modulated radiation therapy (IMRT) can be used to treat certain patients with thyroid cancer. Conventional radiation therapy that is delivered with a machine that directs several high-energy beams at the area of the cancer is called EBRT.

IMRT allows radiation to be delivered more precisely with the use of the following advanced techniques:

• Three-dimensional scans of the cancer help determine where the radiation should be targeted.
• A rotating device delivers radiation from every point around the cancer, rather than only a few points as with conventional radiation therapy.
• Special blocking devices—called leaves—direct the radiation away from sensitive organs and toward the cancer.

IMRT appears to reduce the chance of injury to healthy body structures that are near the cancer while delivering higher doses of radiation to the cancer. In the treatment of thyroid cancer, this means that sensitive cells in the neck area—such as the cells that line the throat—may be spared from radiation damage, reducing side effects and improving quality of life.

Findings reported by researchers in New York suggest that IMRT is an effective treatment for select cases of thyroid cancer.

Systemic Therapy: Precision Cancer Medicine, Chemotherapy, and Immunotherapy

Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Some patients with early stage cancer already have small amounts of cancer that have spread outside the thyroid. These cancer cells cannot be treated with surgery alone and require systemic treatment to decrease the chance of cancer recurrence.  Advanced stage and recurrent cancers and Anaplastic thyroid cancer that cannot be treated with surgery can only be treated with systemic therapy.  Systemic therapies commonly used in the treatment of thyroid cancer include:

Chemotherapy

Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs, administered through a vein, or delivered orally in the form of a pill. Most chemotherapy drugs cannot tell the difference between a cancer cell and a healthy cell. Therefore, chemotherapy often affects the body’s normal tissues and organs, which can result in complications or side effects. In order to more specifically target the cancer and avoid unwanted side effects researchers are increasingly developing precision cancer medicines.

Precision Cancer Medicines

Through genomic-biomarker testing performed on the cancer or in blood doctors are increasingly able to define the genomic alterations in a cancers DNA that is driving the growth of a specific cancer. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines have been developed for the treatment of thyroid cancers with identifiable cancer driving mutations.

Immuno-oncology

Precision immunotherapy treatment of cancer has also progressed considerably over the past few decades and has now become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, however, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.

Researchers are mainly focused on two promising types of immunotherapy. One type creates a new, individualized treatment for each patient by removing some of the person’s immune cells, altering them genetically to kill cancer, and then infusing them back into the bloodstream the other uses precision medications to enhance the immune systems response to the cancer.

Treatment of Thyroid Cancer by Stage

Stage I-II: Stage I-II thyroid cancers are generally confined to the thyroid, but may include multiple sites of cancer within the thyroid.

Stage III: Stage III thyroid cancer is greater than 4 cm in diameter and is limited to the thyroid or may have minimal spread outside the thyroid. Stage III thyroid cancer is also referred to as locally advanced disease.

Stage IV: Stage IV thyroid cancer has spread beyond the thyroid to the soft tissues of the neck, lymph nodes in the neck, or distant locations in the body.

Recurrent: Thyroid cancer that has recurred after treatment or progressed with treatment is called recurrent disease.

References

1 Cancer Stat Facts: Thyroid Cancer. National Cancer Institute website. Available at: https://seer.cancer.gov/statfacts/html/thyro.html. Accessed January 14, 2017.

2 American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017.

3 Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005. Cancer. 2009;115(16):3801–3807. doi: 10.1002/cncr.24416.

4 Pellegriti G, et al. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013;2013:10. doi: 10.1155/2013/965212.

5 Liska J, et al. Thyroid tumors: histological classification and genetic factors involved in the development of thyroid cancer. Endocr Regul. 2005;39(3):73–83.

6 Tennvall J, Biörklund A, Möller T, et al.: Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer 57 (7): 1405-14, 1986.

7 Khoo ML, Asa SL, Witterick IJ, et al.: Thyroid calcification and its association with thyroid carcinoma. Head Neck 24 (7): 651-5, 2002.

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