Ryan P. Smith, MD
Updated by Caroline Kim, MD & Susan Mandel, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 18, 2012
The thyroid gland is located on the anterior aspect (front) of the neck. It can be felt just below the thyroid cartilage, or "Adam's apple". It is a butterfly shaped organ that stretches across the midline of the neck just below the Adam's apple, with its "wings" spreading superiorly (towards the head) on either side of the Adam's apple. These "wings" are called the lobes of the thyroid, with the portion extending across midline called the isthmus. As an endocrine gland, the thyroid gland produces, stores, and secretes the thyroid hormones thyroxine (T4) and triiodothyronine (T3) into the bloodstream. The thyroid does this as a response to a hormone produced by the pituitary gland called thyroid stimulating hormone, or TSH. When the thyroid gland is "turned on" by TSH, it increases its uptake of iodine, which is required to make thyroid hormone. The principal cells of the thyroid are called follicular cells and are mainly responsible for the production and secretion of thyroid hormones. Thyroid hormone plays an important role in controlling our metabolic rate. Many functions such as body temperature and heart rate are regulated by thyroid hormone. Too much thyroid hormone in your system is called hyperthyroidism while too little is called hypothyroidism. An imbalance of thyroid hormone may cause serious problems if not properly treated.
The definition of a tumor is a mass of abnormally growing cells. Tumors can be either benign or malignant. Benign tumors have uncontrolled cell growth, but without any invasion into normal tissues and without any spread. A malignant tumor is called cancer and these tumor cells have the ability to invade tissues and spread locally as well as to distant parts of the body. It is estimated that there will be 53,000 new cases of thyroid cancer diagnosed in 2012, representing about 1% of all malignancies. The most common types of cancers of the thyroid gland are derived from the thyroid follicular cells, which are responsible for thyroid hormone production. The most common types of thyroid cancers are papillary thyroid cancer (75-80%) and follicular thyroid cancer (about 15%). Papillary thyroid cancer typically has a different appearance under the microscope compared with normal thyroid cells, which allows its diagnosis with fine needle aspiration biopsies of thyroid nodules. Follicular thyroid cancer may closely resemble normal thyroid cells on a biopsy, but as a cancer, has the ability to divide uncontrollably and invade and spread. Papillary and follicular, the two most common types of thyroid cancer, have the highest survival rates.
The next most common type of cancer of the thyroid is called medullary thyroid cancer (5%), which is derived from the parafollicular "C" cells of the thyroid. In about 15% of patients with this cancer, there is a familial genetic predisposition to develop other types of endocrine tumors (see below). Medullary thyroid cancer is more aggressive than papillary or follicular cancer, and is more likely to spread to lymph nodes and outside of the neck.
The other major type of thyroid cancer often described is called anaplastic thyroid cancer (1%). This cancer usually affects older people and is very aggressive. Other rare types of cancers that may be found in the thyroid include: lymphomas (cancer of the lymph gland cells), or metastases (cancers from other sites that have spread to the thyroid gland, such as melanoma, breast cancer, renal cell cancer, or lung cancer). Hürthle cell carcinoma, a variant of follicular thyroid cancer is addressed in a separate article.
Thyroid cancer is fairly common, as small microscopic papillary cancers are found at autopsy in approximately 10-15% of people with no known thyroid disease. However, death due to thyroid cancer is uncommon, with fewer than 1500 deaths per year, explained by the fact that thyroid cancer is usually slow growing, tending to remain localized to the thyroid gland or neck for many years. Most cases of thyroid cancer are sporadic; meaning there is no obvious predisposition or risk factor for development. However, it is more common in women, occurring in a 3:1 ratio. Studies have also shown a preponderance of certain types of thyroid cancer in regions with a high incidence of goiters (enlarged thyroid glands), which occur as a result of a lack of dietary iodine. This is further supported by the decrease of thyroid cancers in population given supplemental iodine.
The most firmly established risk factor for the development of thyroid cancer is exposure to ionizing radiation to the neck region at a young age (18 years old or less). This is supported by the high incidence of thyroid cancer seen in many populations exposed to radiation. Notably, this includes children 18 years or younger treated with radiation therapy for cancers such as Hodgkin's disease or nasopharyngeal cancer, or as part of their therapy to prevent leukemia from spreading to the brain. In addition, children who received total body irradiation in preparation for bone marrow transplantation are also at higher risk. Radiation therapy was also used in the 1940-1960s for benign conditions like acne and this population has an increased risk for thyroid cancer. Children at the time of the atomic blasts at Nagasaki and Hiroshima, or of the Chernobyl nuclear plant explosion in 1986 also have a greater incidence of thyroid cancer. In fact, thyroid cancer is one of the most common cancers noted in populations exposed to large doses of radiation through accident or war. There is usually a delay of at least a few decades between exposure and the development of cancer. However the younger the patient is at the time of radiation exposure, the higher his or her risk is of developing thyroid cancer.
A notable genetic predisposition is associated with medullary thyroid cancer, which is associated with multiple endocrine neoplasia (MEN) type 2 syndrome and familial medullary thyroid cancer. Patients with MEN type 2 may also develop other endocrine tumors in their parathyroid gland and/or adrenal tumors, called pheochromocytoma.
As most cases of thyroid cancers are sporadic and not associated with any risk factors, there is usually no method to prevent the development of thyroid cancer. Careful examination of the thyroid and consideration of screening for patients at high risk could be considered, though the general prevention of thyroid cancers is not possible. In addition, it is important that the thyroid is shielded in children who undergo diagnostic Xray procedures, such as dental Xrays.
The early detection of thyroid cancers is generally through careful visual and physical examination of the neck. Palpation of the neck will detect many clinically significant thyroid cancers, which is part of a routine physical exam. In addition, the thyroid gland is included on many radiology studies performed to evaluate other organs, such as CT scans of the lungs and cervical spine. All patients suspected to have thyroid nodules, either from physical examination or from another radiology study, should have a thyroid ultrasound performed to take a picture of the thyroid. Thyroid ultrasound uses sound waves to image the thyroid gland and surrounding structures. The ultrasound appearance of the nodule can help doctors determine if a fine-needle aspiration biopsy is required to further evaluate the nodule. However, there is no evidence that it is cost-effective to perform ultrasounds to screen for thyroid nodules in the general population. Notably, ultrasound detects the majority of small (<1 cm) incidental thyroid cancers, which are unlikely to affect the survival of most patients-akin to very early stage indolent prostate cancers and non-melanoma skin cancers.
The story can be quite different in patients diagnosed with genetic syndromes with a high risk of medullary thyroid cancer, such as MEN type 2. The present recommendation for the majority of patients with a genetic mutation associated with MEN type 2 is to undergo a prophylactic total thyroidectomy (complete removal of the thyroid) to prevent the development of a possibly aggressive medullary thyroid cancer.
By far, the most common presentation of thyroid cancer is an asymptomatic thyroid nodule, identified on physical exam or found incidentally on a radiologic scan. As the thyroid gland is a fairly superficial organ in the neck, a thyroid nodule could be noticed early, at which time medical attention should be sought. By no means is every thyroid nodule a thyroid cancer. In fact, 95% of thyroid nodules are benign.
Less commonly, thyroid cancer can present as a large mass in the neck. The large mass can be located either in the region of the thyroid, representing the primary thyroid cancer, or in a separate region of the neck, representing a spread of cancer to the lymph nodes. Thyroid tumors can also at times present as hoarseness or with symptoms of tracheal or esophageal compression, such as shortness of breath, air hunger, problems or pain with swallowing, or neck pain.
Once a thyroid nodule is noted, the next steps are all designed to determine if the nodule represents a benign growth or malignant tumor. The most common etiology behind a thyroid nodule is a small portion of benign thyroid tissue, which must be differentiated from a thyroid cancer. Obviously a careful physical exam should be done by a physician, with attention to the examination of the neck to evaluate for the presence of enlarged lymph nodes. Blood tests are performed to determine the function of the thyroid gland. Most patients have normal thyroid function tests.
However if laboratory tests indicate an over-functioning gland then additional tests are performed to determine if the nodule is composed of benign thyroid tissue that is overproducing thyroid hormone. This is important because biopsy is not required for such "functioning" nodules. The test to determine whether a thyroid nodule is functional is a nuclear medicine study with radioactive iodine, called a thyroid scan. This test is efficacious because functioning thyroid tissue takes up iodine to produce normal thyroid hormones. Therefore, the small amount of radioactive iodine used to take pictures will be taken up by those areas of the thyroid that are producing thyroid hormone. Hence, a nodule composed of functioning thyroid tissue will appear "hot" in these nuclear medicine scans (i.e., concentrating the radioactive iodine). These "hot nodules" are almost always benign and often require no further work-up for malignancy. Nodules that are "cold" (i.e., do not take up much iodine) are also often benign, though can be malignant in 15-20% of cases. Therefore, these deserve more attention and further work-up.
However, most patients (>95%) with thyroid nodules have normal thyroid function and the nuclear medicine thyroid scan is not indicated. For these patients, the next step in investigating a nodule is a thyroid ultrasound. Ultrasound has the ability to provide additional information about a nodule, such as its composition (solid or cystic) and its appearance (hypoechoic or dark versus hyperechoic or bright), which may increase or decrease its likelihood of being cancer. In addition ultrasound may detect more suspicious nodules that are not able to be detected on physical exam. Finally ultrasound may also identify abnormal lymph nodes around the thyroid gland, which could be evaluated at the same time as the thyroid nodule. While ultrasound may be considered by some to be a less "advanced" imaging technique, compared to CT or MRI scans, it is an extremely powerful tool in obtaining information about a thyroid nodule.
The ultrasound appearance of a thyroid nodule confers a certain thyroid cancer risk for that nodule. The American Thyroid Association and the American Association of Clinical Endocrinologists have both published evidence-based guidelines that recommend that decision making for which nodules should undergo fine-needle aspiration (FNA) biopsy includes consideration of:
Fine needle aspiration involves placing a thin needle (25 or 27 gauge) into the nodule, and drawing up cells from it so that they can be analyzed. Usually this is done under ultrasound guidance, meaning that an ultrasound is performed at the time of the procedure to visualize the needle placement into the nodule. FNA has a diagnostic accuracy of over 98%, though it is highly dependent on the physician's expertise in performing the test and the pathologist's experience in interpreting the results. Some cancers, such as follicular thyroid cancer, cannot be diagnosed by cytology alone, or a nodule may fall in an "indeterminate" diagnostic category. New molecular-based testing is becoming available to help determine which nodules are benign by their genetic profile. However, surgery is often required for malignant and indeterminate nodules.
If a diagnosis of thyroid cancer is made, additional pre-operative work-up is done to determine if there was spread of disease to local lymph nodes using ultrasound. In some cases, additional imaging of the neck is required by the surgeon using a CT (usually without IV contrast) or, more commonly, MRI of the neck to evaluate lymph nodes, muscle or tracheal involvement. In rare cases, evaluation for metastasis to distant areas of the body including the lungs and bones is done prior to surgery.
The staging of a cancer basically describes how much it is grown before the diagnosis has been made, documenting the extent of disease. Before the staging systems are introduced, first some background on how cancers grow and spread, and therefore advance in stage. Cancers cause problems because they spread and can disrupt the functioning of normal organs. One way thyroid cancers can spread is by local extension to invade through the normal structures in the throat and into adjacent structures in the neck. Although this uncommonly happens in this fairly indolent disease, this invasion can include the tracheal and esophageal extension, causing possible airway compromise and disruption of swallowing function.
Thyroid cancer spreads most commonly by accessing the lymphatic system. The lymphatic circulation is a complete circulation system in the body (somewhat like the blood circulatory system) that drains into various lymph nodes. When cancer cells access this lymphatic circulation, they can travel to lymph nodes and start new sites of cancer. This is called lymphatic spread, and usually denotes a poorer prognosis. Thyroid cancer can commonly spread to the lymph nodes of the neck, though (especially with papillary thyroid cancer) this may not carry a worse outcome. The lymph nodes commonly involved in thyroid cancer are those found in the anterior portion of the neck, called the cervical or jugular lymph node chains. They can be found in front of the large muscles on either side of the neck that contract when the head is turned from side to side. Tumor cells that spread to the jugular lymph nodes can then spread to the "supraclavicular" lymph nodes (found behind the collarbone) and to other lymph nodes in the neck. Eventually, they can spread to lymph nodes in the chest, called the mediastinal lymph nodes. At diagnosis, up to 30% of patients have evidence of thyroid cancer spread found on ultrasound examination of the neck lymph nodes before surgery. This information helps the surgeon determine the optimal surgical procedure for the patient.
Thyroid cancers can also spread through the bloodstream. Cancer cells gain access to distant organs via the bloodstream and the tumors that arise from cells' travel to other organs are called metastases. Cancers of the thyroid generally spread locally or to lymph nodes before spreading distantly through the bloodstream. Hence, the incidence of distant metastases is low, with less than 5% of papillary thyroid cancers showing distant spread and between 5 and 20% of follicular thyroid cancers exhibiting metastases. If spread through the bloodstream does occur, the lungs and bones are the most common organs involved.
The staging system used in thyroid cancer is designed to describe the extent of disease in both the thyroid itself and the neck (with spread to the lymph nodes). The staging system used to describe thyroid tumors is the "TNM system", as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components: T-describing the extent of the "primary" tumor (the tumor in the thyroid itself); N-describing the spread to the lymph nodes; M-describing the spread to other organs (i.e.-metastases).
The "T" stage is as follows:
The "N" stage is as follows:
The "M" stage is as follows:
The overall stage is based on a combination of these T, N, and M parameters as well as age (to emphasize the fact that younger patients have a better prognosis) and type of thyroid cancer (to emphasize that papillary and follicular thyroid cancers have excellent prognoses while anaplastic thyroid cancers have poor prognoses).
Though complicated, these staging systems help physicians determine the extent of the cancer, and therefore make treatment decisions regarding a patient's cancer. The stage of cancer, or extent of disease, is based on the information gathered through the various tests done (described above) as the diagnosis and work-up of the cancer is being performed.
The treatment of thyroid cancer can involve an approach combining surgery, radioactive iodine, radiation therapy, and/or thyroid hormone suppressive therapy, depending on the stage and type of thyroid cancer. Surgery always plays the central role, with the removal of the cancer being key. Usually the surgical procedure is a total thyroidectomy (the removal of the entire thyroid gland) or a near total thyroidectomy (leaving only a small remnant of thyroid tissue with parathyroid glands, which are attached to the thyroid). These more extensive surgical procedures have been shown to be more efficacious than more conservative surgeries, such as the removal of a single lobe of the thyroid gland (lobectomy). An exception to this philosophy can be in patients with small (<1cm) papillary thyroid cancers, where a lobectomy may be appropriate. However, if the thyroid gland is not completely removed at the first surgical procedure, the patient is always at risk for recurrence in the portion of the thyroid left behind. Secondary operations to remove the remaining portion of the thyroid gland can also be performed.
A controversy in the surgical treatment of thyroid cancer is how to address the lymph nodes of the neck. When abnormal lymph nodes are felt on physical exam or found by ultrasound, they are obviously removed. All patients suspected to have thyroid cancer should have an ultrasound to evaluate the lymph nodes in the neck because if thyroid cancer is found to have spread to these lymph nodes, the surgeon will remove the lymph nodes at the same time the thyroid is removed. However, the role of a prophylactic removal of the lymph nodes of the neck when they are not obviously involved is unclear. The lymph nodes very close to the thyroid gland are usually dissected without much difficulty and therefore should be removed. However, comprehensive neck dissections to remove a majority of the lymph nodes of the neck are not indicated unless lymph nodes are known to be involved.
After surgery, depending on the pathologic staging, may patients require additional therapy. The first and simplest is the use of supplemental thyroid hormone following surgery. Patients with near total or total thyroidectomies require supplemental thyroid hormone because the thyroid gland is no longer present. However, thyroid hormone can also act as a thyroid cancer therapy. The standard of care is therefore to give slightly more thyroid hormone than the patient would otherwise require because this has been shown to keep any remaining thyroid cancer "asleep" or inactive through a feedback system. In other words, if the body detects that there is a sufficient amount of thyroid hormone already present (through supplementation), it will not produce signals to "turn on" the thyroid to grow and produce thyroid hormone itself. This can be quite successful in keeping residual thyroid cancers dormant.
As thyroid tissue, and some thyroid cancers, preferentially takes up iodine into their cells as part of normal functioning, the use of radioactive iodine, I-131, (RAI) may also be used to kill any remaining thyroid tissue ("remnant" ablation) and potentially any thyroid cancer cells. The iodine is simply taken up into the cell and the radiation within the radioactive iodine itself is released locally, delivering a lethal dose of radiation to these cells. This treatment works well because normal thyroid cells and some thyroid cancer cells preferentially absorb and retain iodine, so other tissues are rarely affected. However, for the first few days after treatment with RAI, patients emit radiation and should avoid close contact with others. Indications for RAI include tumors with high risk features, such as sizes of >2 cm, invasion of the cancer through the thyroid capsule or into the soft tissues of the neck, spread to the lymph nodes or more distantly, or recurrent disease (thyroid cancer that has come back). RAI can be a very effective therapy in many cases, though some thyroid cancers do not have ability to take up iodine, rendering RAI useless.
Radiation therapy can also be used in the adjuvant setting, if it is felt that the patient has a high risk of recurrence following surgery. High risk features include incomplete resection, spread outside the thyroid gland to soft tissues of the neck or to regional lymph nodes, certain histological subtypes of thyroid cancer, and those cancers that that do not take up RAI. It is also used in many cases of anaplastic thyroid cancer to attempt to halt this aggressive disease. Chemotherapy has not classically been used in the treatment of thyroid cancer. However, chemotherapy drugs such as adriamycin and cisplatin may sometimes be used in treatment of metastatic disease, for anaplastic thyroid cancers, or disease that has progressed through RAI or radiation therapy.
Oral drugs such as sorafenib and sunitinib may be used for certain cases of refractory thyroid cancer. These new drugs belong in the class known as tyrosine kinase inhibitors and work by blocking the signals that tell cells to proliferate. A drug called Vandetanib was approved by the FDA this year for advanced medullary cancer. Vardetanib is also a tyrosine kinase inhibitor. These drugs have side effects such as fatigue, rash, and hypertension but offer options for patients with advanced thyroid cancer. Clinical trials are also available for patients with disease not responsive to conventional therapy.
Overall, surgery is the mainstay of treatment. RAI has been shown to improve the outcome of patients with higher risk disease (specifically for patients with Stage II, III, and IV disease). The vast majority of patients with thyroid cancer are curable using these two modalities Radiation therapy has been shown to be efficacious in certain subsets of patients; namely, those with aggressive types of thyroid cancer, or those with residual disease still present after surgery. Continued research is needed to develop more effective treatment for patients with anaplastic and metastatic thyroid cancer that cannot be treated with RAI.
National Cancer Institute "Thyroid Cancer Treatment"
American Cancer Society.: Cancer Facts and Figures 2010. Atlanta, Ga: American Cancer Society, 2010
National Comprehensive Cancer Network. NCCN Guidelines in Oncology 2010: Thyroid Cancer. Version 1.2010.
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American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper, D. S., Doherty, G. M., Haugen, B. R., Kloos, R. T., Lee, S. L., et al. (2009). Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid : 19(11), 1167-1214.
Cohen E, Needles B, Cullen K, et al. Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol 26: 2008 (May 20 suppl; abstr 6025)
Wells S, Robinson B, Gagel R et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA). J Clin Oncol 28:15s, 2010 (suppl; abstr 5503)
Aug 20, 2014 - Two common genetic variants appear to be associated with an increased risk of papillary and follicular thyroid cancer, according to research published online Feb. 6 in the journal Nature Genetics.
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