Thyroid

About the thyroid gland

The thyroid gland is an endocrine organ, meaning it produces hormones (signaling molecules) and releases them into the blood to regulate other tissues. The thyroid gland is a combination of two different types of endocrine cells: follicular cells which produce thyroid hormone, and the parafollicular C-cells, which produce calcitonin. Thyroid hormone is an essential driver of metabolism and many organ functions. Without adequate thyroid hormone, either due to the gland dwindling production due to disease or from surgery or radiation, a hypothyroid state develops in which an affected individual may begin to become fatigued, gain weight, tolerate cold temperatures poorly, and experience a poor cognitive function and depression. Too much thyroid hormone, either from an overactive thyroid gland (or part of it), or an excess of thyroid hormone replacement medication leads to symptoms of anxiety, jitteriness, tremor, a faster and even irregular heart rate, as well as bone density loss. Thyroid hormone itself contains iodine, which must come from our diet, and the thyroid is the only organ that uses iodine.

The parafollicular C-cells produce calcitonin, which functions to lower the calcium concentration in the blood. (This is distinct from parathyroid hormone, which is produced by the nearby parathyroid glands, and has a much larger role in calcium concentration.)

The thyroid gland is located in the low neck, draped across the windpipe just above the sternum.

Evaluation of a thyroid nodule

Once a thyroid nodule has been identified, a diagnostic ultrasound is the usual next step because this offers good information with virtually no risk. Each thyroid nodule seen on ultrasound may be given a score based on the TI-RADS system to quantify its risk of being cancerous. Low TI-RADS nodules are reassuring, medium TI-RADS nodules may be observed or biopsied, and high TI-RADS nodules are usually biopsied, unless they are very small.

Biopsies are usually done with a small-bore (fine) needle and with use of an ultrasound for accurate sampling. These ultrasound-guided fine needle aspiration biopsies (USGFNABs) are low-risk (albeit a bit uncomfortable) and usually provide useful information. The Bethesda Staging System assigns categories of risk to needle biopsy results. If not enough thyroid cells show up on the microscope slide (Bethesda category I), the specimen is not informative and repeat USGFNAB is typically repeated after allowing the thyroid gland to settle for 3 months. If the USGFNAB result is considered benign (Bethesda category II), then the risk for cancer is less than 2%. On the other end of the spectrum, Bethesda category VI is diagnostic of cancer (97-99% likelihood), and category V is highly suspicious of cancer (60-75% chance). This leaves categories III, and IV, which are a gray zone, really. Category III is considered “atypia of undetermined significance,” with a 5-15% chance of cancer, and category IV is “suspicious for a follicular nodule” which carries a 15-30% chance of cancer. For the middling categories III and IV especially, the overall clinical picture and patient preferences play a role in the decision to operate or re-check a given thyroid nodule.

Types of thyroid cancer

There are four main types of thyroid cancer, with the following percentage incidence:

1. Papillary thyroid carcinoma (75-85% of cases)

2. Follicular thyroid carcinoma (including Hürthle cell carcinoma) (10-20% of cases)

3. Medullary thyroid carcinoma (5-8% of cases)

4. Anaplastic thyroid carcinoma (1-2% of cases)

Survival rate is dependent on the type of thyroid cancer and the extent of cancer at the time of diagnosis. Generally, survival rates for papillary and follicular thyroid carcinoma are excellent, that for medullary is good, and for anaplastic is poor. These survival rates are for all-comers, who typically undergo current recommended treatment, so these outcomes do not necessarily apply if an individual were to opt for no treatment or pursue unconventional treatment.

Follicular thyroid carcinoma (including Hürthle cell carcinoma)

Second most common and second least aggressive is follicular thyroid carcinoma (FTC). One nuance about this type of cancer is that a needle biopsy cannot differentiate between a benign follicular adenoma and FTC (which is cancerous). The reason for this is that both the benign and cancerous follicular neoplasms have lots of follicular cells present, but only the cancerous FTC has invasion into the capsule (boundary) of the nodule itself and nearby blood vessels. These features are not seen on a needle biopsy specimen because there are too few cells and the cells are not in their normal spacial relationship when obtained by a needle biopsy. This leads to the Bethesda category IV noted above, which has a 15-30% chance of cancer. FTC can spread to other parts of the body, but has less tendency to do so than with papillary thyroid carcinoma, and when it does, it has lower likelihood of spreading to lymph nodes of the neck and higher likelihood of spreading to other areas, such as the lungs.

Since needle biopsy results may suggest a middling 15-30% chance of cancer, surgery to remove only the part of the thyroid containing that nodule is most common. This provides a definitive diagnosis of either the presence or absence of cancer, and if none is present, the remainder of the thyroid has been spared of unnecessary removal. If pathology does show cancer to be present, however, a thyroid physician may recommend a second operation to remove the remainder of the thyroid gland.

Hurthle cell thyroid carcinoma (HTC) is considered a variant of follicular cell carcinoma. HTC, as a whole, is more aggressive than other follicular carcinomas with greater risk of multiple sites present in the thyroid and spread to the lymph nodes, and is less responsive to radioactive iodine. Initial surgery for HTC is therefore typically to remove the entire thyroid gland.

Medullary thyroid carcinoma

Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin. Cancers of this type produce an abnormally high amount of calcitonin. Approximately 25% of medullary thyroid cancer cases are inherited, caused by an inherited mutation in the RET proto-oncogene, and for this reason, when a new diagnosis of medullary thyroid carcinoma is made, the patient and their immediate family members should have the RET gene tested by genetic sequencing. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50% probability of inheriting the mutant RET proto-oncogene from the affected parent. DNA analysis makes it possible to identify children who carry the mutant gene; surgical removal of the thyroid in children who carry the mutant gene is curative if the entire thyroid gland is removed at an early age, before there is spread of the tumor. The parathyroid tumors and pheochromocytomas are removed when they cause clinical symptoms. For the approximately 75% of medullary thyroid cancers that are sporadic (not familial), a mutation in the RET proto-oncogene is still the cause of the cancer, but rather than inheriting a mutated version of the gene from the sperm or egg, whereby every cell in the body contains a replica of the mutated RET proto-oncogene, the non-familial medullary thyroid carcinoma arises from a mutation in a single parafollicular C cell, which then divides to two cells, then four, and so on. Since the mutation causing familial cases is present at the moment of conception, and sporadic cases occurs at some point in the lifeline, sporadic cases tend to arise at an older age than familial cases. And since familial cases affect every copy of the RET proto-oncogene in the body, other tumors in endocrine glands are likely, a condition called Multiple Endocrine Neoplasia type 2. Parathyroid glands and adrenal glands are susceptible to tumor formation from this genetic mutation and these tumors produce an excess of their respective hormones (parathyroid hormone and epinephrine/norepinephrine, respectively). A plasma level of metanephrines is checked before surgical thyroidectomy takes place to evaluate for the presence of pheochromocytoma, since undiagnosed pheochromocytoma leads to a very high risk of dangerously high blood pressure during surgery and, potentially, death.

While the increased serum concentration of calcitonin is not harmful, it is useful as a marker which can be tested in blood. Diagnosis is primarily accomplished when a fine needle aspiration of the lesion of the thyroid is performed and a pathologist identifies the cancer based on the microscopic appearance of the cells. Identifying individuals at risk for medullary thyroid carcinoma could be done by a blood test for elevated calcitonin levels, but the high cost of performing that test on the population makes it financially infeasible (in the United States).

As with all cancers, medullary thyroid carcinoma has the potential to spread (metastasize) to other parts of the body. Common sites of spread include lymph nodes in the neck, lymph nodes in the central portion of the chest (mediastinum), liver, lung, and bone. Spread to other sites such as skin or brain occurs but is uncommon.

Surgery is the main treatment for medullary thyroid carcinoma, and radiation therapy and cancer medicines are added for patients at high risk of tumor recurrence or those with unresectable disease.

A total thyroidectomy with bilateral neck dissection is the gold standard for treating medullary thyroid cancer, and is the most definitive means of achieving a cure in patients without distant metastases or extensive nodal involvement.

Unlike other types of differentiated thyroid carcinoma (papillary thyroid carcinoma and follicular thyroid carcinoma), there is no role for radioiodine treatment in medullary-type disease. External beam radiotherapy is recommended when there is a high risk of regional recurrence after optimum surgical treatment. A class of drugs called protein kinase inhibitors which block the abnormal kinase proteins involved in the development and growth of medullary cancer cells, have shown evidence of response in 10-30% of patients, and among them, there has been less than a 30% decrease in tumor mass.

The prognosis correlated with the rate at which the postoperative calcitonin concentration doubles, termed the calcitonin doubling time (CDT), rather than the pre- or postoperative absolute calcitonin level.

A second marker, carcinoembryonic antigen (CEA), produced by medullary thyroid carcinoma and other cancers, is released into the blood and it is useful as a blood tumor marker. In general, measurement of serum CEA is less sensitive than serum calcitonin for detecting the presence of a tumor, but has less minute to minute variability and is therefore useful as an indicator of tumor mass.

All comers, the overall 5-year survival rate for medullary thyroid cancer is about 85% and the 10-year survival rate is 75%.

By overall cancer staging into stages I to IV, the 5-year survival rate is 100% at stage I, 98% at stage II, 81% at stage III and 28% at stage IV. The prognosis of MTC is poorer than that of follicular and papillary thyroid cancer when it has metastasized (spread) beyond the thyroid gland.

Anaplastic thyroid carcinoma

Anaplastic thyroid cancer (ATC), also known as anaplastic thyroid carcinoma, is an aggressive form of thyroid cancer characterized by uncontrolled growth of cells in the thyroid gland. This form of cancer generally carries a very poor prognosis due to its aggressive behavior and resistance to cancer treatments. The cells of anaplastic thyroid cancer are highly abnormal and usually no longer resemble the original thyroid cells and have poor differentiation.

ATC is an uncommon form of thyroid cancer only accounting for 1-2% of cases, but due to its high mortality, is responsible for 20-50% of deaths from thyroid cancer. The median survival time after diagnosis is three to six months. It occurs more commonly in women than in men and is seen most commonly in people ages 40 to 70.

Radioactive iodine scan

The radioactive iodine uptake test is a type of diagnostic imaging study used in the diagnosis of thyroid problems, particularly hyperthyroidism and thyroid cancer. It works on the principle that only one type of tissue in the body, thyroid tissue, concentrates iodine. Radioactive iodine acts exactly like normal iodine in the way the body processes it but for a short period of time, it emits radiation that can be detected by a scanner. Areas in which iodine concentrates highly show up on the resultant image. A completely normal thyroid gland, for example, would appear on the resultant image with an even distribution of radioactivity in the shape of the thyroid gland. If a thyroid gland has a particular nodule that is more metabolically active than the remainder of the gland, this nodule would show up as a greater collection of radioactivity against a background of lesser activity outlining the remainder of the thyroid gland. Maximizing uptake of iodine in thyroid tissue is assisted by the patient eating a low iodine diet and not getting any iodine contrast for a CT scan for several weeks before the study so that the thyroid cells are running low on iodine and very “hungry” or avid for iodine at the time of the scan. Having a high level of thyroid stimulating hormone (TSH) also helps this test by “revving up” or increasing metabolic activity of thyroid cells. High TSH can be accomplished by allowing the patient to become hypothyroid over weeks or months before the scan (by not taking any thyroid replacement hormone pills) or by using a newer recombinant TSH that can be given shortly before the uptake scan.

When looking for thyroid cancer with a radioactive iodine uptake test, good information is available if the thyroid gland has already been surgically removed (in a total thyroidectomy). If even one lobe of the thyroid gland were still anatomically present when performing a radioactive iodine test, this remaining thyroid tissue would soak up the vast majority of radioactive iodine, making smaller collections of thyroid tissue (cancerous spread to one or more lymph nodes or the lungs, for example) much less likely to be detected. Thus, a radioactive iodine uptake scan is useful after a total thyroidectomy has been performed. Occasionally, due to ongoing mutations accumulated over multiple generations of multiplying thyroid cancer cells, their behaviors change, which may include a change in the cells’ uptake of iodine. When thyroid cancer cells no longer absorb iodine, then a radioactive iodine test will no longer effectively identify these cancer cells. A PET-CT scan becomes more useful in that scenario.

The process of undertaking a radioactive iodine uptake scan involves the patient swallowing a radioisotope of iodine in the form of capsule or fluid, and the absorption (uptake) of this radiotracer by the thyroid is measured after 4–6 hours and after 24 hours with the aid of a scintillation counter detector in the radiology department.

There are two different radioactive isotopes of iodine that are used in radioiodine uptake scans. 123-I has a shorter half-life than 131-I (a half day vs. 8.1 days), so use of 123-I exposes the body to less radiation, at the expense of less time to evaluate delayed scan images. Furthermore, 123-I emits gamma radiation, while 131-I emits gamma and beta radiation. The radiologist typically chooses one and arranges the timing of events.

The diagnostic radioactive scan It is different from therapeutic radioactive iodine therapy in that the latter uses a much higher dose of radioactive iodine to destroy thyroid cancer cells.

Radioactive iodine ablation (treatment)

The concept behind using radioactive iodine to destroy thyroid cells is clever: since iodine is taken up from the bloodstream preferentially by thyroid cells, and since cells treat radioactive isotopes of iodine identically to non-radioactive iodine, providing radioactive iodine to thyroid cells allows for the radioactivity to be delivered to thyroid cells, wherever they may be. Iodine-131 is often chosen as the isotope of choice for radioiodine ablation because it emits beta particles (electrons) to damage the tissues within a very short range (i.e., within millimeters). This short range effect protects tissues further away from thyroid cells. When radio iodine ablation is taken (either by pill or liquid), the iodine circulates throughout the body and is taken up or incorporated into thyroid cells, wherever they may be. Usually, one or more target areas of known thyroid tissue are already known prior to undertaking radioactive iodine ablation, identified by a radioactive thyroid uptake scan (see above), but in the case of thyroid cancer where some areas of spread may small and undetectable, radioactive iodine ablation can treat those areas.

A few limitations to the effectiveness of radioiodine must be kept in mind, however. A full thyroid gland cannot be completely shut down by radioactive iodine. At best, it can be stunted with radioiodine, which may be all that is needed in cases of hyperthyroidism. In the case of thyroid cancer, however, all cancerous cells need to be eliminated. Radioactive iodine is therefore not an effective primary means of treating thyroid cancer, but it can be of great use after optimal surgical therapy, in which its job is to treat small (microscopic) clusters of thyroid cells not removed by the surgeon. One additional caveat is that as cancer cells divide and give rise to subsequent generations of cancer cells, mutations continue to accumulate. There is a time in which thyroid cancer cells stop acting like thyroid cells and no longer take up iodine. When this happens, these thyroid cancer cells will not be detectable by a radioiodine scan and will not be treatable with radioiodine ablation. When thyroid cancer cells convert to being non-avid for iodine, identification of areas involved with thyroid cancer may be detected with a PET-CT scan.

The principal advantage of radioiodine treatment for hyperthyroidism is that it tends to have a much higher success rate than medications. Depending on the dose of radioiodine chosen, and the disease under treatment (Graves' vs. toxic goiter, vs. hot nodule etc.), the success rate in achieving definitive resolution of the hyperthyroidism may vary from 75-100%. A major expected side-effect of radioiodine in people with Graves' disease is the development of lifelong hypothyroidism, requiring daily treatment with thyroid hormone. On occasion, some people may require more than one radioactive treatment, depending on the type of disease present, the size of the thyroid, and the initial dose administered.

People with graves' disease manifesting moderate or severe Graves' ophthalmopathy (eye disease) are cautioned against radioactive iodine-131 treatment, since it has been shown to exacerbate existing thyroid eye disease. People with mild or no ophthalmic symptoms can limit their risk with a concurrent six-week course of a steroid (such as prednisone). The mechanisms proposed for this side effect involve a TSH receptor common to both thyrocytes (thyroid cells) and retro-orbital tissue.

As radioactive iodine treatment results in the destruction of thyroid tissue, there is often a transient period of several days to weeks when the symptoms of hyperthyroidism may actually worsen following radioactive iodine therapy. In general, this happens as a result of thyroid hormones being released into the blood following the radioactive iodine-mediated destruction of thyroid cells that contain thyroid hormone. In some people, treatment with medications such as beta blockers (propranolol, atenolol, etc.) may be useful during this period of time.

Women breastfeeding should discontinue breastfeeding for at least a week, and likely longer, following radioactive iodine treatment, as small amounts of radioactive iodine may be found in breast milk even several weeks after the radioactive iodine treatment, and this would have the unwanted effect of treating the nursing baby’s thyroid.

A common outcome following radioiodine is a swing from hyperthyroidism to the easily treatable hypothyroidism, which occurs in 78% of those treated for Graves' thyrotoxicosis and in 40% of those with toxic multinodular goiter or solitary toxic adenoma.  Use of higher doses of radioiodine reduces the number of cases of treatment failure, with the trade off for higher response to treatment consisting mostly of higher rates of eventual hypothyroidism which requires daily oral hormone treatment for life.

Additional links

• Thyroid diseases described on the American Head and Neck Society website.

• Link to the American Cancer Society website with information on thyroid cancer.

• Algorithms for Thyroid Nodules