What is Thyroid cancer?

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 when these tumor cells gain the propensity to invade tissues and spread locally as well as to distant parts of the body. In this sense, thyroid cancer occurs when cells of the thyroid gland grow uncontrollably to form tumors that can invade the tissues of the neck, spread to the surrounding lymph nodes, or to the bloodstream and then to other parts of the body. The most common types of cancers of the thyroid gland are derived from the cells responsible for thyroid hormone production. The general term for cancers that come from glandular tissue is adenocarcinoma. In the thyroid, the most common types of cancer are papillary adenocarcinoma of the thyroid (75-80%) and follicular adenocarcinoma of the thyroid (~15%). Papillary thyroid cancer takes on a folded appearance under the microscope, which eases its diagnosis. Follicular thyroid cancer may closely resemble normal thyroid tissue, but as a malignancy, has a propensity to divide uncontrollably and invade and spread. The next most common type of cancer of the thyroid is called medullary thyroid cancer (5%), which is derived from the parafollicular cells of the thyroid. This is often associated with a familial genetic predisposition to develop certain types of cancers (see below). The other major type of thyroid cancer often described is called anaplastic thyroid cancer (2%). This cancer usually affects older people and is very aggressive. Other types of cancers, such as lymphomas (cancer of the lymph gland cells), sarcomas (cancer of soft tissues such as muscle or cartilage cells), or metastases (cancers from other sites that have spread to the thyroid gland) are also seen in the thyroid gland.

Am I at risk for thyroid cancer?

Thyroid cancer is fairly common, as it is found at autopsy in approximately 5% of people with no known thyroid disease. However, death due to thyroid cancer is uncommon, explained by the fact that thyroid cancer is usually an indolent disease, tending to remain localized to the thyroid gland 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. This has prompted studies into the investigation of estrogen as a possible risk factor for thyroid cancer, though this has never been proven. 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. This is supported by the high incidence of thyroid cancer seen in many populations exposed to radiation. Notably, this includes patients with Graves' disease (a hyperthyroid condition) treated with radiation, Hodgkin's disease patients treated with radiation, survivors of atomic blasts at Nagasaki and Hiroshima, and survivors of the Chernobyl explosion. In fact, thyroid cancer is one of the most common cancers noted in populations exposed to large doses of radiation through accident or war.

A notable genetic predisposition is associated with medullary thyroid cancer, which is associated with a syndrome called multiple endocrine neoplasia (MEN) type 2 syndrome. Patients with MEN type 2 (Sippler's syndrome) have a strong familial history of medullary thyroid cancers and a type of adrenal cancer, called pheochromocytoma.

How can I prevent thyroid cancer?

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 impossible.

What screening tests are available?

Ultrasound testing has been proven to detect thyroid nodules-benign or malignant-of sizes of less than 1 cm. However, using ultrasound for mass screening is not likely to be efficacious because of the incidences and natural history of thyroid cancer. Notably, the majority of thyroid cancers are papillary thyroid cancer, which are historically very indolent cancers. Therefore, the small tumors that ultrasound has the ability to detect are likely to be very small papillary 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. Hence, the early detection of thyroid cancers is generally through careful physical examination of the neck. Palpation of the neck will detect most clinically significant thyroid cancers.

Obviously, the story can be quite different in patients diagnosed with MEN type 2 and the subsequent high risk of medullary thyroid cancer. The present recommendation for patients with the 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.

What are the signs of thyroid cancer?

By far, the most common presentation of thyroid cancer is a solitary nodule on the thyroid, which can be felt on physical exam. 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, most represent hyperplasia (benign growth of the thyroid) of the thyroid gland.

Less commonly, thyroid cancer can present as multiple nodules in the thyroid or 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.

How is thyroid cancer diagnosed and staged?

Any thyroid nodule deserves attention. 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 functioning 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 attempt to detect enlarge lymph nodes. Other laboratory tests are also usually done to determine the function of the thyroid gland. Tests that indicate an over-functioning gland point more toward the nodule being composed of benign functional tissue. A test to determine the etiology of a thyroid nodule is a nuclear medicine study with radioactive iodine. This test is efficacious because functioning thyroid tissue takes up iodine to produce normal thyroid hormones. Therefore, radioactive iodine will be preferentially taken up by normally functioning thyroid tissue and will show up on tests that are designed to detect radioactivity. Hence, a nodule composed of functioning thyroid tissue will appear "hot" in these nuclear medicine scans (i.e., expelling a large amount of radioactivity because of the concentration of active thyroid tissue). These "hot nodules" are almost always benign and often require no further work-up. 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 especially deserve more attention and further work-up.

The first step in investigating a suspicious or cold nodule, and often the definitive step in diagnosis, is a fine needle aspiration (FNA), which involves placing a needle into the nodule and drawing up cells from it so that they can be analyzed. FNAs have a diagnostic accuracy of over 98%, though it is highly dependent on the physician's expertise in performing the test. After a diagnosis is made, further work-up is done to determine if there was spread of disease to the local lymph nodes and distant areas of the body including the lungs and bones. Hence, this includes a CT scan of the neck to evaluate lymph nodes and an MRI of the neck to evaluate muscle or tracheal involvement. Some also recommend a bone scan and chest x-ray, as thyroid cancer can (rarely) metastasize to the bones and lungs.

Staging

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.

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:
T1-tumor 1 cm or less within the thyroid gland
T2-tumor sized 1-4 cm within the thyroid gland
T3-tumor size greater than 4 cm within the thyroid gland
T4-tumor of any size extending outside of the thyroid gland itself

The "N" stage is as follows:
N0-no spread to lymph nodes
N1-tumor spread to lymph nodes
N1a-spread to lymph nodes on the same side of the neck as the primary tumor
N1b-spread to lymph nodes bilaterally or to the opposite side of the primary tumor

The "M" stage is as follows:
M0-no tumor spread to other organs
M1-tumor spread to other organs

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).

Papillary or Follicular Thyroid Cancer, age > 45 years
Stage I-T1, N0, M0
Stage II-T2-3, N0, M0
Stage III-T4, N0, M0 or any N1, M0
Stage IV-any M1

Papillary or Follicular Thyroid Cancer, age <45 years
Stage I-any M0
Stage II-any M1

Medullary Thyroid Cancer, any age
Stage I-T1, N0, M0
Stage II-T2, N0, M0
Stage III-any N1, M0
Stage IV-any M1

Anaplastic Thyroid Cancer, any age
ALL designated as Stage IV to denote the aggressiveness of anaplastic thyroid cancer

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.

What are the treatments for thyroid cancer?

The treatment of thyroid cancer can involve an approach combining surgery, radioactive iodine and radiation 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 thryroidectomy (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, Stage I 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 be performed to attempt to salvage a cure in these patients, though the complication rates in these "completion thyroidectomies" may be high.

A controversy in the surgical treatment of thyroid cancer is how to address the lymph nodes of the neck. When lymph nodes are felt on physical exam or found by ultrasound, they are obviously 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, most would agree that radical neck dissections to remove a majority of the lymph nodes of the neck are not indicated unless lymph nodes are known to be involved.

In more advanced cases of thyroid cancers, surgical treatment is not enough, and patients require various adjuvant therapies. The first and simplest is the use of supplemental thyroid hormone following surgery. Patients with near total or total thyroidectomies are likely to be hypothyroid anyway, hence requiring supplemental thyroid hormone regardless of the state of the cancer. The standard of care is therefore to use this supplemental thyroid hormone in order to keep the remaining thyroid gland (or 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 create hormone itself. This can be quite successful in keeping residual thyroid cancers dormant.

As thyroid tissue (and often thyroid cancers) preferentially take up iodine into their cells as part of normal functioning, the use of radioactive iodine (RAI) can be used to kill any remaining 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 the cancer cells. Indications for RAI include tumors with high risk features such as sizes of >1.5 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 there are thyroid tumors that do not 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 alone. It is often used in patients with papillary, follicular, or medullary thyroid cancer with high risk features, such as incomplete resection or spread outside the thyroid gland to soft tissues of the neck or to regional lymph nodes that do not take up RAI. It is also used in all cases of anaplastic thyroid cancer to attempt to halt this aggressive disease. In practice, the most common indications for radiation therapy are when the thyroid cancer is adherent to the trachea, has mediastinal lymph node involvement, or does not take up RAI. In these cases, radiation therapy has been proven to decrease the risk of local recurrences. Also, a rare type of papillary thyroid cancer called "Tall Cell Variant" has a very high risk of recurrence after surgery. Radiation therapy is also indicated for this type of thyroid cancer.

Chemotherapy has not classically been used in the treatment of thyroid cancer. However, chemotherapy drugs such as adriamycin, cisplatin, and etoposide have been used in anaplastic thyroid cancers or disease that has progressed through RAI or radiation therapy.

Overall, surgery is the mainstay of treatment. RAI has been shown to improve the outcome of patients with higher risk disease (basically anyone with greater than Stage I disease). Radiation therapy has been shown to be efficacious in certain subsets of patients; namely, those with aggressive types of thyroid cancer, those with more advanced disease who do not respond to RAI, or those with residual disease still present after surgery. The vast majority of patients with thyroid cancer are curable using these modalities. However, further research is needed in patients who do not respond to conventional therapy and in patients with poor prognosis anaplastic disease.