The thyroid gland is in the throat, below the larynx (Adam’s apple). It comprises two lobes that sit on either side of the windpipe, joined at the front by an isthmus. The thyroid gland secretes hormones that regulate many metabolic processes, such as growth and energy expenditure. Around one out of every 1,000 people will be affected by thyroid cancer, with women slightly more susceptible than men. Risk factors include chronic goitre, family history, gender and exposure to radiation, particularly if the doses were given specifically to the head and neck. In the 1950s, radiation therapy was often used to treat problems of the adenoids and tonsils. Nuclear fallout is also associated with thyroid cancer. There are different types of thyroid cancer, categorised by malignancy, growth rate and the type of cells affected. Recovery depends on various factors including the age and general health of the person, the type and location of the cancer, and how far the cancer has advanced before commencement of treatment.

Symptoms
The symptoms of thyroid cancer depend on the type, but may include:

—      Swelling of the throat as the thyroid gland enlarges

—      Hoarse voice

—      Voice changes

—      Persistent cough

—      Gastrointestinal disturbances, such as diarrhoea or constipation.

Different types

The types of thyroid cancer are:

—      Papillary carcinoma - the most common form of thyroid cancer, which accounts for 70 to 80 per cent of cases. This cancer affects the cells that produce thyroid hormone. It grows slowly.

—      Follicular carcinoma - this cancer also affects thyroid hormone-producing cells. However, it grows more quickly. This cancer accounts for around 10 per cent of thyroid cancers.

—      Medullary carcinoma - this type of cancer tends to run in families. The symptoms may mimic those of Cushing’s syndrome. It does not involve thyroid hormone-producing cells and accounts for 5 to 10 per cent of thyroid cancers.

—      Anaplastic carcinoma - this is the most aggressive and malignant form of thyroid cancer. It tends to grow rapidly and block the windpipe. It generally originates in benign or low grade cancerous thyroid tumours and accounts for around 7 per cent of thyroid cancers.

—      Thyroid lymphoma - this occurs when white blood cells (lymphocytes) invade the thyroid and become cancerous. This accounts for around 4 per cent of thyroid cancers.

Risk factors

Anyone can develop thyroid cancer, regardless of age or gender. Some of the risk factors associated with thyroid cancer include:

—      Radiation exposure - high doses of radiation were used during the 1950s to treat disorders of the throat and skin. Absorbed radioactive fallout following nuclear accidents is also a risk factor.

—      Chronic goitre –persistent enlargement of the thyroid gland.

—      Family history - a susceptibility can be inherited.

—      Gender - more women than men develop thyroid cancer.

Diagnosis methods

Diagnosing thyroid cancer involves a number of tests, including:

—      Physical examination

—      Blood tests

—      Ultrasound scans

—      Examination of the vocal cords

—      Tissue biopsy.

Treatment options

Treatment depends on the type, size and stage of the cancer, and the patient’s age and health. Options may include:

—      Surgery - the favoured treatment for papillary, follicular and medullary cancers. The thyroid gland is removed, either whole or in part depending on the size of the cancer and how much of the gland is affected. Nearby lymph nodes may also be removed.

—      Radiation therapy - Radioactive iodine is used to kill any remaining thyroid hormone-producing cells. This normally requires the patient to stop thyroxine treatment for a few weeks to cause thyroid stimulating hormone (TSH) levels to rise and thereby stimulate the thyroid cells to absorb the radioactive iodine. Patients can become significantly hypothyroid during this period. External radiation is frequently used for medullary and anaplastic cancer, and for tumours which do not respond to radioactive iodine.

—      Hormone therapy - patients require thyroid hormone replacement in the form of thyroxine following surgery. The doses given are generally higher than for other hypothyroid patients, in order to suppress the production of thyroid stimulating hormone and thereby suppress the growth of thyroid cells.

—      Chemotherapy - drugs that kill cancer cells are used for the cancers that do not involve the thyroid hormone-producing cells.

Genetic testing

Medullary carcinoma has been associated with an abnormal gene that can be inherited. Blood relatives of someone diagnosed with medullary carcinoma can be genetically tested. A person who has the gene, but not the cancer, may elect to have their thyroid gland removed to rule out any possibility of developing the disease in the future.

Where to get help

—      Your doctor

—      Thyroid Australia Tel. (03) 9888 2588

—      Cancer Council Victoria, Information and Support Service Tel. 131 120

Things to remember

—      The thyroid gland regulates many bodily functions including growth and energy expenditure.

—      There are four different types of thyroid cancer, which are categorised according to their malignancy and speed of growth.

—      Treatment options may include surgery to remove the thyroid gland and nearby lymph nodes, chemotherapy, radiation therapy and hormone therapy.

Thyroid cancer is readily treatable and has excellent survival rates

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The thyroid gland is the biggest gland in the neck. It is situated in the anterior (front) neck below the skin and muscle layers. The thyroid gland takes the shape of a butterfly with the two wings being represented by the left and right thyroid lobes which wrap around the trachea. The sole function of the thyroid is to make thyroid hormone. This hormone has an effect on nearly all tissues of the body where it increases cellular activity. The function of the thyroid therefore is to regulate the body’s metabolism thyroid cancer tumor surgery operation condition thyroid parathyroid disease disease tumor

Common Thyroid Problems

The thyroid gland is prone to several very distinct problems, some of which are extremely common. These problems can be broken down into [1] those concerning the production of hormone (too much, or too little), [2] those due to increased growth of the thyroid causing compression of important neck structures or simply appearing as a mass in the neck, [3] the formation of nodules or lumps within the thyroid which are worrisome for the presence of thyroid cancer, and [4] those which are cancerous. Each thyroid topic is addressed separately and illustrated with actual patient x-rays and pictures to make them easier to understand. The information on this web site is arranged to give you more detailed and complex information as you read further.

—      Goiters ~ A thyroid goiter is a dramatic enlargement of the thyroid gland. Goiters are often removed because of cosmetic reasons or, more commonly, because they compress other vital structures of the neck including the trachea and the esophagus making breathing and swallowing difficult. Sometimes goiters will actually grow into the chest where they can cause trouble as well. Several nice x-rays will help explain all types of thyroid goiter problems.

—      Thyroid Cancer ~ Thyroid cancer is a fairly common malignancy, however, the vast majority have excellent long term survival. We now include a separate page on the characteristics of each type of thyroid cancer and its typical treatment, follow-up, and prognosis. Over 30 pages thyroid cancer.

—      Solitary Thyroid Nodules ~ There are several characteristics of solitary nodules of the thyroid which make them suspicious for malignancy. Although as many as 50% of the population will have a nodule somewhere in their thyroid, the overwhelming majority of these are benign. Occasionally, thyroid nodules can take on characteristics of malignancy and require either a needle biopsy or surgical excision. Now includes risks of radiation exposure and the role of Needle Biopsy for evaluating a thyroid nodule. Also a new page on the role of ultrasound in diagnosing thyroid nodules and masses.

—      Hyperthyroidism ~ Hyperthyroidism means too much thyroid hormone. Current methods used for treating a hyperthyroid patient are radioactive iodine, anti-thyroid drugs, or surgery. Each method has advantages and disadvantages and is selected for individual patients. Many times the situation will suggest that all three methods are appropriate, while other circumstances will dictate a single best therapeutic option. Surgery is the least common treatment selected for hyperthyroidism. The different causes of hyperthyroidism are covered in detail.

—      Hypothyroidism ~ Hypothyroidism means too little thyroid hormone and is a common problem. In fact, hypothyroidism is often present for a number of years before it is recognized and treated. There are several common causes, each of which are covered in detail. Hypothyroidism can even be associated with pregnancy. Treatment for all types of hypothyroidism is usually straightforward.

—      Thyroiditis ~ Thyroiditis is an inflammatory process ongoing within the thyroid gland. Thyroiditis can present with a number of symptoms such as fever and pain, but it can also present as subtle findings of hypo or hyper-thyroidism. There are a number of causes, some more common than others. Each is covered on this site.

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Introduction

The thyroid is a small gland that is located at the base of your throat, just below the larynx. It has two lobes and is one of several glands that make up the endocrine system. This system produces hormones that help your body to function properly. The thyroid gland absorbs iodine from the diet, which is found in fish, seafood and dairy products. It also produces two hormones; thyroxine (T4) and triiodothyronine (T3) which help keep the body functioning normally.

In the UK, approximately 1,400 people are diagnosed with thyroid cancer each year. It is a fairly rare type of cancer that develops slowly and is usually more common in middle-aged and older people. However, there is one type, known as papillary thyroid cancer, which often affects younger people. Overall, more women get thyroid cancer than men. It rarely affects children.

The four main types of thyroid cancer are:

—      papillary the most common type and it tends to affect younger people,

—      follicular is less common, and is usually found in older people,

—      medullary - is rare and can sometimes run in families, and

—      anaplastic is rare, is more common in older people, it grows quickly, and unlike other types of thyroid cancer, can be difficult to treat.

The outlook for most types of thyroid cancer is usually very good, and many people are completely cured of the disease, even if it has spread beyond the thyroid.

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Thyroid cancer is a group of malignant tumors that originate from the thyroid gland. The thyroid is a gland in the front of the neck. The thyroid gland absorbs iodine from the bloodstream so it can produce thyroid hormone (it regulates body metabolism and temperature, it affects the heart rate, and its lack is associated with decrease in energy levels or fatigue). The thyroid gland contains two types of cells: follicular cells, which are responsible for the production of thyroid hormone; and C cells, which make calcitonin, a hormone that participates in the calcium metabolism.

A healthy thyroid gland is barely palpable. A normal gland has two lobes on each side of the windpipe, joined by a narrow strip of tissue called the isthmus. If a mass develops in the thyroid, it is felt as a lump in the neck. A diffusely swollen thyroid gland is called a goiter, which may be due to iodine deficiency. The gland is located on the trachea (windpipe) just below the larynx (voice box) Thyroid tissue growths are known as nodules. Ninety percent (90%) of all thyroid growths are benign and ten percent (10%) of thyroid nodules are malignant. Cancer cells can spread into neighboring tissues and organs, and enter the lymphatic system and the bloodstream.

Here are four types of thyroid cancer:

Papillary Thyroid Cancer - Papillary cancer develops in the follicular cells and grows slowly. It is usually found in one lobe; only 10% to 20% of papillary cancers appear in both lobes.

Follicular Thyroid Cancer - Follicular cancer also develops in the follicular cells and grows slowly, yet is less common. When detected early, it can be treated successfully.

Papillary and follicular cancers make up 80% to 90% of thyroid cancers, and are grouped under the term differentiated thyroid cancer. When detected early, especially in people below the age of 45-50 years, it can be treated successfully.

Medullary Thyroid Cancer - Medullary cancer develops in the C cells. It can be controlled if it is found and treated before it spreads to other parts of the body. Medullary cancer accounts for 5% to 10% of thyroid cancers.

Anaplastic Thyroid Cancer - This is a very rare and aggressive form of thyroid cancer that takes its origin from differentiated thyroid cancer or other benign tumors of the gland, and in its giant cell variety is often rapidly fatal.

As we well know, there are many kinds of cancer; unfortunately they all come about because of the out-of-control growth of abnormal cells.

Healthy Cells vs. Cancer Cells

Healthy cells are like a cat.  They need structure to determine the size of bones and shape of the body, tail and whiskers. The DNA in genes and chromosomes determine this. They need energy to play and prowl and sustain life. This is derived from chemicals in food. Cats need a system to deliver chemicals (food nutrients like amino acids, carbohydrates, fats, vitamins and minerals) to all parts of their body. These are the blood vessels. Growth factors take a kitten into a lazy old cat, all the while helping it to function normally.

The body and its cells are mostly made up of protein. The building blocks of proteins are substances called amino acids that in the form of enzymes and hormones literally control every chemical reaction within the cells. When these are modified, different messages are sent to a complex control system that can alter their function. There are twenty different kinds of amino acids that are essential to life. Twelve of these can be synthesized within the body however; eight must be supplied by the daily diet.

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Thyroid cancer is more common among women than men and accounts for only 1 percent of all cancers diagnosed in the United States. Most thyroid cancers grow slowly but certain types can be aggressive.

There are four major types of thyroid gland cancer — anaplastic, follicular, medullary and papillary. These types of thyroid cancer look differently under a microscope and generally grow at varying rates.

—      Anaplastic cancer: Anaplastic cancer is the fastest growing type of thyroid cancer. The cancer cells are extremely abnormal and spread rapidly to other parts of the body. Anaplastic cancers make up only about 2 percent of all thyroid cancers and are generally difficult to cure.

—      Follicular cancer: This type of cancer also develops in thyroid cells that produce iodine-containing hormones. Most follicular cancers can be cured. About 10 percent to 30 percent of thyroid cancers are follicular cancers. These cancers are well differentiated, meaning slow growing and contain cells that are similar to healthy thyroid cells.

—      Medullary cancer: Medullary cancer is more difficult to control than papillary and follicular thyroid cancer. The cells involved in medullary cancers produce calcitonin, a hormone that does not contain iodine. About 5 to 7 percent of all thyroid cancers are medullary cancers. Of the four types of thyroid cancer, only medullary thyroid cancer can be inherited, which is caused by an alteration in the RET gene. Individuals who inherit this alteration are almost certain to develop medullary thyroid cancer at some time in their lives.

—      Papillary cancer: This type of thyroid cancer develops in cells that produce thyroid hormones containing iodine. Papillary cancer is well-differentiated, meaning that it grows very slowly and contains cells that are similar to healthy thyroid cells. Doctors usually can treat these cancers successfully, even when cancer cells have spread to nearby lymph nodes. Papillary cancers account for about 60 percent to 80 percent of all thyroid cancers and have a favorable prognosis.

The most common symptom of thyroid cancer is a lump, or nodule, that can be felt in the thyroid gland or neck. Other symptoms are rare. Pain is seldom an early warning sign of thyroid cancer. You may have a tight or full feeling in the neck, difficulty breathing or swallowing, hoarseness or swollen lymph nodes.

Reviewed by health care specialists at UCSF Medical Center.

Last updated May 8, 2007

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When I was diagnosed with papillary thyroid cancer in 1997 at the age of 35, my life was changed forever. Now, 10 years later, I am still going strong and fighting this rare disease, finding strength and courage by looking for whatever good I can find in the bad.

One of the amazing things that has happened to me as a result of the cancer is that when I went “hypothyroid” (off my thyroid hormone for several weeks) for a scan, I discovered I could rewrite the lyrics to songs and make them relate to thyroid cancer. Suddenly I was able to rhyme and find humor in a very black situation.

I shared my first song with the members of an on-line thyroid cancer support group, and the response was great. We had a good laugh, and talked about how important a positive attitude is in fighting cancer.

I wrote more songs and shared them with my on-line “thyca” friends. They started sharing the songs with their loved ones, and they began to tell me what a difference the songs had made in their lives:

“Thanks for the first laugh I have had since I was diagnosed.”

“Your songs are hilarious!”

“My husband and I read your songs on the computer and laughed until we cried. Now he understands a little better what I am going through. Thank you.”

Most of the songs are just plain funny. Some of them are powerful, intense, and could be called “black humor”. But whatever category they fit in, all of my songs are written from my own experiences, and the stories of my on-line cancer survivor friends.

This site is dedicated to my beloved grandmother, Joan Farrell, who bought me the computer that helped change my life. She loved to hear how the Internet brought me information, friends, and a place to share my experiences and songs with others.

I’d also like to send my sincere thanks to my friends at ComSite International, Inc., for sponsoring this site.

And to all thyroid cancer survivors who thought they were the only ones out there, you are not alone. Welcome.

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What is it?

Thyroid cancer is a disease of the thyroid gland in which the cells become abnormal and form tumors. Located at the base of the throat, the thyroid gland makes hormones that regulate heart rate, blood pressure, body temperature, and metabolism. There are four different types of thyroid cancer: papillary, follicular, medullary, and anaplastic thyroid. The cancers grow at different rates, so the aggressiveness of each cancer is different. If left untreated, the cancer can spread to other parts of the body.

Who gets it?

Thyroid cancer is three times as common in women as in men. The rate of thyroid cancer is also higher in whites than in African Americans. Most people who develop thyroid cancer are 50 years of age or older, but the disease can affect teenagers and young adults. Thyroid cancer accounts for 1% of all cancers.

What causes it?

Although the exact cause of thyroid cancer has not been determined, exposure to radiation during childhood is a known risk factor for thyroid cancer. In the 1950s and 1960s, radiation was used to treat acne and to reduce swelling and infection of organs in the neck, such as the tonsils, adenoids, and lymph nodes. Recent studies prove that people who received radiation to the head and neck during their childhood have a higher than average chance of developing thyroid cancer.

What are the symptoms?

The most common symptom of thyroid cancer is a lump or nodule in the thyroid gland that can be felt in the neck. Occasionally, a patient will have a swollen lymph node in the neck and hoarseness due to pressure from the tumor on the nerve to the voice box (recurrent laryngeal nerve). A patient may also have difficulty swallowing or breathing due to a tumor obstructing the esophagus or windpipe.

How is it diagnosed?

Several tests, including x-ray examination, transillumination of the gland, radioisotope scanning, needle biopsy and ultrasonic examination, may be performed by a doctor to determine size and location of the tumor and to determine whether it is non-cancerous (benign) or cancerous (malignant). If malignant, thyroid cancer can be diagnosed as one of four types. The most common type of thyroid cancer is papillary cancer, a slow-growing cancer that can usually be treated successfully. The second type, follicular cancer, also has a good cure rate. However, if follicular cancer invades blood vessels or grows into nearby structures in the neck, it may be difficult to control. About 30-50% of thyroid cancers are follicular cancers. Medullary cancers are more difficult to control because they have a tendency to spread to other parts of the body. About 5-7% of all thyroid cancers are medullary cancers. Anaplastic cancer is the fastest growing of all thyroid cancers, however only 2% of all thyroid cancers are anaplastic.

What is the treatment?

Treatment of thyroid cancer depends on the type of cancer and its stage. The most common treatments used are surgical removal, radiation therapy, hormone therapy and chemotherapy. If the cancer has not spread to distant parts of the body, surgical removal is the usual treatment. Radiation therapy may be used after surgery to kill cancer cells and shrink tumors. Hormone therapy is another treatment used to stop the cancer cells from growing. If the cancer has spread to other parts of the body and surgery is not possible, chemotherapy treatment may be used to kill or slow the growth of cancer cells throughout the body.

Self-care tips

Because most people with thyroid cancer have no known risk factors, it is not possible to completely prevent this disease. However, periodic follow-up examinations are essential for patients who have had surgery for papillary or follicular thyroid cancer, because recurrences sometimes occur many years after apparently successful surgery. In addition, the National Cancer Institute recommends that a doctor examine anyone who has received radiation to the head and neck during childhood at intervals of one or two years.

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Thyroid malignancy occurs with relative infrequency in the United States, though benign thyroid disease is relatively common. Although patients with thyroid cancers generally have a favorable prognosis compared with that of patients with many other solid tumors, an estimated 1200 patients died of thyroid cancer in the United States in 1998.  Contemporary treatment of patients with thyroid malignancy requires a multidisciplinary approach involving an endocrinologist, a thyroid surgeon, a radiologist, and, on occasion, medical and radiation oncologists.

For excellent patient education resources, visit eMedicine’s Endocrine System Center. Also, see eMedicine’s patient education article Thyroid Problems.

Frequency

Thyroid cancers represent approximately 1% of new cancer diagnoses each year. Approximately 23,500 cases of thyroid cancer are diagnosed yearly in the United States. The incidence of thyroid malignancies is 3 times higher in women than in men. The incidence of this disease peaks in the third and fourth decades of life.

Thyroid cancers are divided into papillary carcinomas, follicular carcinomas, medullary thyroid carcinomas (MTCs), anaplastic carcinomas, primary thyroid lymphomas, and primary thyroid sarcomas. Papillary carcinoma represents 80% of all thyroid neoplasms. Follicular carcinoma is the second most common thyroid cancer, accounting for approximately 10% of cases. MTCs represent 5-10% of neoplasms. Anaplastic carcinomas account for 1-2%. Primary lymphomas and sarcomas are rare.

Etiology

Thyroid carcinomas arise from the 2 cell types present in the thyroid gland. The endodermally derived follicular cell gives rise to papillary, follicular, and probably anaplastic carcinomas. The neuroendocrine-derived calcitonin-producing C cell gives rise to MTCs. Thyroid lymphomas arise from intrathyroid lymphoid tissue, whereas sarcomas likely arise from connective tissue in the thyroid gland.

Radiation exposure significantly increases the risk for thyroid malignancies, particularly papillary thyroid carcinoma. This finding was observed in children exposed to radiation after the nuclear bombings in Hiroshima and Nagasaki during World War II. Additional evidence was gathered after atomic bombs were tested in the Marshall Islands, after the accident at the Chernobyl nuclear power plant, and in patients who received low-dose radiation therapy for benign disorders (eg, acne, adenotonsillar hypertrophy). Low-dose radiation exposure from imaging studies has not been found to have a tumorigenic effect. Radiation targeting the thyroid gland (eg, iodine-131 ablation of the thyroid) or high-dose external-beam radiation therapy does not appear to increase the risk of papillary thyroid carcinoma. This is presumably because cell killing increases with these doses.

Low dietary intake of iodine does not increase the incidence of thyroid cancers overall. However, populations with low dietary iodine intake have a high proportion of follicular and anaplastic carcinomas.

History

Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid nodule. Patients or physicians discover most of these nodules during routine palpation of the neck. Palpable thyroid nodules are present in approximately 4-7% of the general population, and most represent benign disease. High-resolution ultrasonography reportedly depicts thyroid nodules in 19-67% of randomly selected individuals. An estimated 5-10% of solitary thyroid nodules are malignant. Palpable and nonpalpable nodules of similar size have the same risk of malignancy.

The patient’s age at presentation is important because solitary nodules are most likely to be malignant in patients older than 60 years and in patients younger than 30 years. In addition, thyroid nodules are associated with an increased rate of malignancy in male individuals. Growth of a nodule may suggest malignancy. Rapid growth is an ominous sign.

Malignant thyroid nodules are usually painless. Sudden onset of pain is more strongly associated with benign disease, such as hemorrhage into a benign cyst or subacute viral thyroiditis, than with malignancy.

Hoarseness suggests involvement of the recurrent laryngeal nerve and vocal fold paralysis. Dysphagia may be a sign of impingement of the digestive tract. Heat intolerance and palpitations suggest autonomously functioning nodules.

Medullary carcinoma can occur as part of multiple endocrine neoplasia (MEN) 2A or 2B syndrome, as well as familial MTC (FMTC) syndrome. Patients with a family history of thyroid cancer should be evaluated with vigilance.

Physical examination

Physical examination should include thorough head and neck examination with careful attention to the thyroid gland and cervical soft tissues, as well as indirect laryngoscopy.

Solitary thyroid nodules can vary from soft to hard. Hard and fixed nodules are more suggestive of malignancy than supple mobile nodules are. Thyroid carcinoma is usually nontender to palpation. Firm cervical masses are highly suggestive of regional lymph node metastases. Vocal fold paralysis implies involvement of the recurrent laryngeal nerve.

EVALUATION AND MANAGEMENT OF THE SOLITARY THYROID NODULE

Section 4 of 11 

—      Authors and Editors

—      Introduction

—      Clinical Presentation

—      Evaluation and Management of the Solitary Thyroid Nodule

—      Well-Differentiated Thyroid Carcinoma

—      Hürthle Cell Carcinomas

—      Medullary Thyroid Carcinoma

—      Anaplastic Carcinoma and Other Thyroid Carcinomas

—      Technique of Thyroidectomy

—      Multimedia

—      References

The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign disease and, thus, to determine which patients require intervention and which patients may be monitored serially. History taking, physical examination, laboratory evaluation, and fine-needle aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules. Imaging studies can be adjuncts in select cases.

Fine-needle aspiration biopsy

FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the first intervention. The technique is inexpensive and easy to perform, and it causes few complications.

To perform FNAB, comfortably position both the patient and the physician. Extend the patient’s neck slightly and palpate the nodule with the nondominant hand. Clean the skin with alcohol and infiltrate the area with local anesthesia. Place a 21- to 25-gauge needle on the end of a syringe. Many physicians use trigger-style aspirating handles on the syringe. Introduce 2 mL of air into the syringe, and place the needle into the skin. Apply negative pressure to the syringe, and pass the needle through the nodule, which is identified by using the nondominant hand. After several passes, release the negative pressure, and withdraw the needle. Use the air remaining in the syringe to expel the specimen from the hub and needle onto a glass slide or into cytologic solution for a cell block. Fix the slide in alcohol for Papanicolaou and hematoxylin-eosin staining. Some slides can be air dried and stained with Romanowsky stain (Diff-Quick).

Successful diagnosis by the cytologist depends on accurate sampling of the nodule and specimen cellularity. For this reason, several authors recommend performing at least 3 aspirations to ensure adequacy of the specimen and to minimize false-negative results. Ultrasonographic guidance can help to increase the accuracy of FNAB. Danese et al report increased false-negative rates with palpation FNAB compared with ultrasonography-guided FNAB.

The 4 results from FNAB are benign disease, malignant disease, indeterminate for diagnosis, and nondiagnostic. In their review of several large series, Gharib and Goellner (1993) found that 69% of FNAB results were benign, 4% were malignant, 10% were indeterminate, and 17% were nondiagnostic. Their false-positive rate was 2.9%, and their false-negative rate was 5.2%. Sensitivity and specificity were 83% and 92%, respectively.

Results of FNAB determine the next step in managing the thyroid nodule. A definitive diagnosis is obtained in as many as 50% of repeated biopsies. Patients whose findings are nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for tissue diagnosis, or they can be monitored clinically. In these circumstances, radioiodine scans can be useful for determining the functional status of the nodule, as most hyperfunctioning nodules are benign.

Indeterminate biopsy findings are labeled suspicious at some institutions. When cellular material is adequate for evaluation but when malignant and benign disease cannot be differentiated, biopsy results can be labeled suspicious. Patients with a suspicious diagnosis should undergo lobectomy for definitive diagnosis.

Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and MTC are often positively identified on the basis of FNAB results alone. In patients with these carcinomas, definitive surgical planning can be undertaken at the outset. However, it is nearly impossible to distinguish a follicular adenoma from a follicular carcinoma on the basis of FNAB findings. Patients with follicular neoplasm, as determined with FNAB results, should undergo surgery for thyroid lobectomy for tissue diagnosis. These patients require complete thyroidectomy if a malignancy is discovered on review of the pathology. Some controversy exists regarding the extent of thyroidectomy (total thyroidectomy, subtotal thyroidectomy, or lobectomy) for a particular pathologic diagnosis. Each pathologic diagnosis and its corresponding extent of thyroidectomy are discussed below. 

Complications of FNAB are few and generally minor. The most common complications are minor hematoma, ecchymosis, and local discomfort. Clinically significant hematoma and swelling is exceedingly rare. Inadvertent puncture of the trachea, carotid artery, or jugular vein usually does not cause clinically significant problems and is managed with the application of local pressure.

Laboratory evaluation

The serum thyroid-stimulating hormone (TSH) concentration is a highly sensitive measure for hyperthyroidism or hypothyroidism. A sensitive TSH assay is useful in the evaluation of solitary thyroid nodules. A low serum TSH value suggests an autonomously functioning nodule, which typically is benign. However, malignant disease cannot be ruled out on the basis of low or high TSH levels.

Other thyroid function tests are usually not necessary in the initial workup.  Serum thyroglobulin measurements are not helpful diagnostically because they are elevated in most benign thyroid conditions.

Elevated serum calcitonin levels are highly suggestive of MTC. Serum calcitonin measurement, which was once the mainstay in the diagnosis of FMTC, has been replaced by sensitive polymerase chain reaction (PCR) assays for germline mutations in the RET proto-oncogene. These mutations are present in patients with MEN 2A, MEN 2B, and FMTC (see Genetic testing for MEN and FMTC in the Medullary Thyroid Carcinoma section). However, calcitonin and the more sensitive pentagastrin-stimulated calcitonin are used as tumor markers to monitor patients who have been treated for MTC. Because of the low incidence of MTC overall, testing of serum calcitonin is not a cost-effective screening tool in the primary workup of thyroid nodules.

Imaging procedures

Ultrasonography is the imaging modality most commonly used to evaluate thyroid disease. This noninvasive study enables accurate evaluation of the thyroid gland. However, the usefulness of ultrasonography for distinguish between malignant and benign nodules is limited. Simple cysts found on sonograms are benign, but simple cysts are rarely found. Cysts are most commonly complex, with at least some solid component that could potentially harbor malignancy. Microcalcifications noted on sonograms are associated with thyroid malignancy. Ultrasonography is highly sensitive for thyroid nodules and can depict nodules only a few millimeters in size.

A sonogram ordered to evaluate a solitary nodule often reveals additional nodules of questionable clinical significance. The accuracy of FNAB results increases when sonographic guidance is used. Use of ultrasonography-guided FNAB can be useful for biopsy of small or difficult-to-palpate thyroid nodules as well as for FNAB of nodules in children. Ultrasonography can also be useful for accurate measurement of thyroid nodules that are being monitored serially.

Radioiodine imaging can help in determining the functional status of a nodule. Nonfunctional nodules do not take up radiolabeled iodine-123 and appear as cold spots in the thyroid (cold nodules). Hyperfunctioning nodules take up radioiodine and appear as hot spots (hot nodules). Warm nodules appear similar to the surrounding normal thyroid tissue. Hot or warm nodules were historically thought to be benign; therefore, they did not require further evaluation for malignancy. However, in a review of 5000 patients undergoing thyroidectomy regardless of radioimaging findings, Ashcraft and Van Herle (1981) found that 4% of hot nodules harbored malignancy.

Carcinoma cannot be excluded on the basis of radioiodine scans. Therefore, radioiodine scans are usually not helpful for the routine evaluation of thyroid nodules. In select situations, radioiodine studies can be diagnostic adjuncts. When results of repeated FNAB of a nodule are nondiagnostic, a radioiodine imaging can help in directing management if a hot nodule is to be monitored clinically.

CT scanning and MRI can be used to evaluate soft-tissue extension of large or suspicious thyroid masses into the neck, trachea, or esophagus and to assess metastases to the cervical lymph nodes. These studies do not have a role in the routine management of solitary thyroid nodules. The use of iodinated contrast agents should be avoided in patients with possible thyroid carcinoma because they interfere with the postoperative use of radioactive iodine.

WELL-DIFFERENTIATED THYROID CARCINOMA

—      Authors and Editors

—      Introduction

—      Clinical Presentation

—      Evaluation and Management of the Solitary Thyroid Nodule

—      Well-Differentiated Thyroid Carcinoma

—      Hürthle Cell Carcinomas

—      Medullary Thyroid Carcinoma

—      Anaplastic Carcinoma and Other Thyroid Carcinomas

—      Technique of Thyroidectomy

—      Multimedia

—      References

Papillary carcinoma

Clinical features

Papillary carcinoma is the most common thyroid malignancy, representing approximately 80%. Papillary carcinoma and follicular carcinoma make up the well-differentiated thyroid carcinomas. Women develop papillary cancer 3 times more frequently than men do, and the mean age at presentation is 34-40 years.

Cases can occur familially, either alone or in association with Gardner syndrome (familial adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is associated with the development of papillary thyroid carcinoma. Tumors typically appear after a latency period of about 10-20 years. In addition, an increased incidence of papillary cancer is hypothesized among patients with Hashimoto thyroiditis (chronic lymphocytic thyroiditis). Despite this possibility, the rate of malignancy for a given nodule in people with Hashimoto thyroiditis is similar to that of individuals with a normal gland.

Papillary carcinoma is a slow-growing tumor that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid. The cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation. This feature has both diagnostic and therapeutic value for managing residual disease and recurrences after surgical excision (see Treatment and Prognosis below).

Pathology

On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with ill-defined margins. Under microscopy, the tumors are unencapsulated neoplasms that characteristically grow with papillae consisting of neoplastic epithelium overlying fibrovascular stalks. Very differentiated tumors can have a complex arborizing pattern. Nuclei have an empty ground-glass appearance with characteristic nuclear grooves and pseudoinclusions. Mitoses are rare.

Another histologic feature is the presence of psammoma bodies, which occur in 50% of papillary carcinomas. Psammoma bodies are calcific concretions that have a circular laminated appearance. They are found in the stroma of the tumor. In addition, many papillary carcinomas contain areas that show a follicular growth pattern. However, when the nuclear features in follicular areas are the same as those in papillary areas, the tumor behaves like a classic papillary carcinoma and should be designated as such. Papillary carcinoma may be multicentric, with foci present in both the ipsilateral and contralateral lobes.

Local invasion

Tumors can grow directly through the thyroid capsule to invade surrounding structures. Growth into the trachea can occur, producing hemoptysis. Extensive involvement can cause airway obstruction. The recurrent laryngeal nerves can become involved because of their proximity in the tracheoesophageal groove. Patients present with a hoarse, breathy voice and, occasionally, dysphagia.

Regional and metastatic disease

Another common feature of papillary carcinoma is its propensity to spread to the cervical lymph nodes. Clinically evident lymph node metastases are present in approximately one third of patients at presentation. Microscopic metastases are present in one half. The most common site of lymph node involvement is in the central compartment (level 6) located medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases. This finding has important implications on the treatment algorithm for patients in this situation (see Treatment and Prognosis below and Images 1-2).

Approximately 5-10% of patients develop distant metastases. Distant spread of papillary carcinoma typically affects the lungs and bone.

Follicular carcinoma

Clinical features

Follicular carcinoma is the second most common thyroid malignancy and represents about 10% of thyroid cancers. Follicular carcinoma represents an increased portion of thyroid cancers in regions where dietary intake of iodine is low. Similar to papillary carcinoma, follicular carcinoma occurs 3 times more frequently in women than in men. Patients with follicular carcinoma are typically older than those with papillary carcinoma at presents. The mean age range at diagnosis is late in the fourth to sixth decades.

Like papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically (see Postoperative radioiodine scanning and ablation below).

Pathology

On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms. Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the tumors contain neoplastic follicular cells, which overall can have a solid, trabecular, or follicular growth pattern (that usually produces microfollicles). The follicular cells in these tumors do not have characteristic features like papillary carcinoma cells.

Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsule invasion and/or vascular invasion. For this reason, differentiating follicular adenomas from follicular carcinomas is extremely difficult with FNAB cytology and frozen section analysis. The tumors are divided into minimally invasive and widely invasive lesions depending on the histologic evidence of capsule and vascular invasion. Immunohistochemical staining for thyroglobulin and cytokeratins is nearly always positive.

Local invasion

Local invasion can occur as it does with papillary carcinoma, with the same presenting features (see Local invasion for Papillary Carcinoma, above).

Cervical and distant metastases

Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis is significantly increased (approximately 20%). Lung and bone are the most common sites.

Treatment and prognosis

Surgical treatment

The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. In this procedure, all apparent thyroid tissue is surgically removed. Major complications in this procedure are recurrent laryngeal nerve injury and hypoparathyroidism from inadvertent damage or removal of the parathyroid glands. Complications associated with total thyroidectomy are discussed in the Technique of Thyroidectomy section below.

After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant metastatic disease (see Postoperative radioiodine scanning and ablation below), followed by radioablation of any residual disease found.

Over the years, modifications to total thyroidectomy have been proposed in an effort to reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total thyroidectomy. Subtotal thyroidectomy has been proffered as an alternative to total thyroidectomy. With subtotal thyroidectomy, a small portion of gross thyroid tissue opposite the side of malignancy is left in place to minimize the risk of injuring the recurrent laryngeal nerve and of inadvertently removing the parathyroid glands on that side. Patients usually receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid tissue.

With improved stratification of patients into prognostic groups (see Prognostic factors below), some surgeons have proposed thyroid lobectomy with isthmectomy alone as definitive treatment for patients at low risk for recurrent or metastatic disease. This approach remains to be substantiated as a feasible alternative to total thyroidectomy.

Management of the neck

The neck must be thoroughly examined for lymphatic metastases. Ultrasonography of the neck with particular attention to the central compartment (level 6) is an effective diagnostic approach. FNAB of suspicious lymph nodes can be performed. Cervical metastases discovered preoperatively or intraoperatively should be removed by means of en bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while sparing the nonlymphatic structures. Excision of single nodes, known as berry picking, is inadequate therapy for metastatic disease. Elective neck dissection (removal of clinically benign neck lymphatic tissue) in a well-differentiated carcinoma is not indicated because postoperative radioiodine treatment effectively treats microscopic lymphatic metastases.

Postoperative radioiodine scanning and ablation

Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH sensitive and because they take up iodine, radioiodine preferentially targets residual normal or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to ablate this tissue. After thyroidectomy, use of radioiodine scanning and ablation has become commonplace for diagnosing and treating residual thyroid tissue, as well as regional and distant metastases from well-differentiated thyroid carcinomas. Pretherapeutic iodine-uptake scanning is controversial because of its cost and because of concerns about ¹³¹I-induced tumor stunning, which may decrease the effectiveness of radioiodine treatment.

After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or triiodothyronine (T3, Cytomel). ¹³¹I or ¹²³I scanning is performed when the patient is in a hypothyroid state (TSH >30-50).  Approximately 4-6 weeks after thyroidectomy, hypothyroid can be induced by discontinuing replacement (T4 for 4 weeks or T3 for 2 weeks) to obtain high serum TSH levels. A diagnostic dose of ¹³¹I or ¹²³I is given initially. Whole-body scanning is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or metastatic disease is detected, a therapeutic dose of ¹³¹I is administered to ablate the tissue. Posttreatment scanning should also be performed because it may reveal metastatic disease not otherwise noted.

The role of recombinant human TSH (Thyrogen) in remnant ablation continues to evolve. Thyrogen is approved for postsurgical remnant ablation in Europe but not the United States. Barbaro et al found equivalent results in postsurgical remnant ablation when they compared traditional T4 withdrawal with the discontinuation of T4 1 day before TSH stimulation. Thyrogen stimulation avoids the discomfort of patients having to discontinue thyroid replacement and is especially useful in those unable to tolerate hypothyroidism or to generate a high TSH level.

If a treatment dose of ¹³¹I is required, diagnostic thyroid scanning is repeated while the patient is in the hypothyroid state about 6 months after initial treatment. Again, if the diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated until the diagnostic scan is negative.

A promising new development for follow-up thyroid scanning is the use of recombinant human TSH as opposed to withdrawing T4 to increase autogenous TSH levels. This approach avoids the discomfort of having to discontinue thyroid replacement therapy for these scans.

Thyroid suppression

After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are maintained on thyroid-suppression suppression. Patients take T4 in daily doses sufficient to suppress TSH production by the pituitary. Low TSH levels in the bloodstream reduce tumoral growth rates and reduce recurrence rates of well-differentiated thyroid carcinomas. The extent to which TSH should be suppressed is controversial. Most authors recommend reducing TSH levels to 0.1 mU/L. This level provides adequate thyroid suppression while avoiding deleterious cardiac and bone effects of profound thyroid suppression.

Follow-up care

Patients are regularly monitored every 6-12 months with serial radioiodine scanning and serum thyroglobulin measurements after surgery and radioiodine therapy. Thyroglobulin is a useful marker of tumor recurrence because well-differentiated thyroid cancers synthesize thyroglobulin. However, it is useful only after total thyroid ablation. Serum thyroglobulin is measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin antibody levels should be obtained with each thyroglobulin measurement. Rising thyroglobulin level after thyroid ablation suggests recurrence. Ultrasonography of the neck can also be used to detect regional recurrences.

Management of recurrence

Recurrences are best treated with surgical excision if the disease is clinically evident and surgically accessible. Nonlocalized recurrences detected on the basis of elevated thyroglobulin levels are treated with ¹³¹I. On occasion, recurrent tumors do not concentrate iodine. Positron emission tomography (PET) may be helpful in localizing disease in such circumstances. When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may be useful. Chemotherapy, usually with doxorubicin, is reserved for tumors that do no respond to other treatments and for palliative care. Response rates of 35-40% are reported, though complete responses to chemotherapy are rare.

Prognostic factors

The long-term disease-free survival with aggressive treatment and management is nearly 90% overall. A variety of factors are associated with prognosis, as listed below.

—      Age: The patient’s age at diagnosis is one of the most important prognostic features of well-differentiated thyroid carcinoma. Cancer-related death is most likely to occur if the patient is >40 years at the time of diagnosis. Recurrences are most common in patients whose disease is diagnosed when they were <20 years or >60 years.

—      Sex: Men are twice as likely as women to die from thyroid cancer.

—      Size: The size of the primary tumor is related to survival. Patients with primary tumors >4 cm have increased recurrence and cancer-related mortality rates.

—      Histology: Overall, papillary carcinoma is associated a 30-year cancer-related death rate of 6%. Follicular carcinoma has a 30-year cancer-related death rate of 15%.