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Thyroid Disorders & Treatments Nodules & Cancer

Cancer of the Thyroid: Papillary & Follicular

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The diagnosis of cancer is terrifying for most patients because it has become associated in our minds with pain and death. But, in fact, the outlook for patients with thyroid cancer is usually excellent because: 1) most thyroid cancer is easily curable with surgery, 2) it causes little pain or disability, and 3) novel and effective means of diagnosis and therapy are available for several kinds of thyroid cancer.

Thyroid cancer usually presents itself as a lump or nodule in the thyroid gland. However, it should be emphasized that most thyroid nodules (95% or more) are benign. Unfortunately, it may be difficult to distinguish a benign from a malignant nodule on the basis of history and physical examination, even with the help of laboratory tests including blood hormone levels and scans (images) of the thyroid gland. Therefore, biopsy of thyroid nodules (generally Fine Needle Aspiration, FNA) provides the most valuable information in helping a physician to determine whether a surgical operation is necessary.

Occasionally, a thyroid cancer can present as a swollen lymph node in the neck, as hoarseness due to pressure from the tumor on the nerve to the voice box (recurrent laryngeal nerve), or as difficulty in swallowing or breathing due to a tumor obstructing the esophagus or windpipe. Rarely it presents as disease which has spread to another part of the body (metastatic disease).

In this review, we will discuss the most common types of thyroid malignancy.

What is Well-Differentiated Thyroid Cancer?

A cancer is a malignant tumor which grows in the body. A well-differentiated cancer is one which superficially looks like the normal parent tissue, in this case the thyroid gland. There are two types of well-differentiated thyroid cancer, papillary and follicular, both derived from the normal thyroid cell, the follicular cell.

Well-differentiated thyroid cancers account for about 90% of all thyroid malignancies and most are associated with an excellent outlook. Although we do not know exactly what causes these well-differentiated cancers to grow, we do know that they are more likely to develop in patients who have received x-ray treatments in childhood for enlarged tonsils, enlarged thymus glands, acne, and occasionally for other malignancies such as Hodgkin's disease. An important epidemic of papillary carcinoma developed in the region surrounding Chernobyl after the nuclear power plant melt-down. Routine diagnostic x-rays (like chest x-rays, dental x-rays, or thyroid scans) do not cause such thyroid cancer.

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What is Papillary Thyroid Cancer?

A papilla is a nipple-like projection. Papillary cancers have multiple projections giving them a fern or frond-like appearance under the microscope. In addition the nuclei (central portion of the cells) are changed compared to normal thyroid cell nuclei. Tiny, microscopic areas of papillary cancer can be found in up to 10% of "normal" thyroid glands, when thyroid tissue is carefully examined with a microscope. The more carefully a pathologist looks for these tiny cancers, the more commonly they are found. These microscopic cancers seem to have no clinical importance and are more a curiosity than a disease. In other words, there does not seem to be a tendency for these small cancer-like growths to enlarge and become more serious malignant tumors.

On the other hand, when papillary cancer grows large enough to form a lump in the thyroid gland, we consider it clinically important, for it is likely to continue to enlarge and may spread elsewhere in the body. Papillary tumors make up about 70% to 80% of all thyroid cancers, and can occur at any age. There are only about 12,000 new cases of papillary cancer in the United States each year, but because these patients have such a long life expectancy, we estimate that one in a thousand people have or have had this form of cancer.

Papillary cancer tends to grow slowly and to spread by means of the lymphatic system to lymph glands in the neck. In fact, in about one third of the patients who undergo surgery for papillary cancer, the tumor has already spread to surrounding lymph glands (lymph node metastases). Fortunately, the generally excellent outlook is usually not altered by lymph gland metastases. Some clinicians believe that the presence of abnormal lymph nodes on both sides of the neck or abnormal lymph nodes in the chest area does worsen the prognosis.

The outlook or prognosis for patients with papillary thyroid carcinoma is determined by several features at the time of diagnosis. Many different staging systems have been used, without consensus among experts. Based on the Mayo Clinic system, the most favorable characteristic is a primary tumor confined to the thyroid itself (intrathyroidal). As noted above, the presence or absence of lymph gland involvement usually does not affect the prognosis. The 85% of patients with intrathyroidal papillary carcinoma have a 25-year mortality rate of 1%. This means that only 1 out of every 100 such patients will be dead of thyroid cancer 25 years later.

Since the outlook in patients with intrathyroidal primary tumors is so favorable, it is important that therapy not be more hazardous than the disease. Radical surgery is rarely indicated for this mild type of papillary cancer. Ten percent or more of patients with intrathyroidal papillary cancer will have a subsequent recurrence. Fortunately recurrences generally occur as enlarged lymph glands in the neck and are not life-threatening. Such recurrences are usually removed surgically.

The prognosis is not as good in patients where the cancer has grown through the thyroid into surrounding tissues (extrathyroidal). Specifically, this means spread through the fibrous capsule that surrounds the thyroid gland into the tissues of the neck. Lymph node involvement is not considered extrathyroidal spread. In a very small percentage of patients (about 5%), the cancer eventually spreads through the blood stream to distant sites, particularly the lungs and bones. These distant tumor sites (metastases) can often be treated with radioactive iodine but they are difficult to cure (see below).

Young patients who have papillary thyroid cancer generally have an excellent prognosis (outlook). However, patients under the age of 20 have a higher risk of spread to the lungs and of local recurrence. The prognosis is also not as good in those older than age 50 and those with larger tumors (particularly greater than 3.5 to 4 cm. [around 1.5 inches in diameter]).

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What is Follicular Thyroid Cancer?

The normal thyroid gland is made up of sphere-shaped structures called follicles, which are lined by thyroid follicular cells. When a thyroid cancer resembles these normal structures, the cancer is called a follicular cancer. Follicular cancer makes up about 10% of all thyroid cancers in the United States, and tends to occur in somewhat older patients than papillary carcinoma.

Although follicular cancer of the thyroid is generally considered to be more aggressive than papillary cancer, this is not always true. Approximately one third of these patients have a minimally invasive follicular thyroid carcinoma. Since the follicular cells look just like normal thyroid cells, the diagnosis of cancer depends on finding these cells where they do not belong. Follicular carcinoma is considered minimally invasive when the cells grow through the lining (capsule) of the nodule or at most into a few blood vessels. The outcome is excellent in minimally invasive follicular carcinoma, particularly those diagnosed with capsular invasion alone. On the other hand, when the follicular cancer extensively invades blood vessels, the prognosis is worse and spread to distant sites including the lungs and bones is common. In general, the prognosis is better in younger patients than in those over 50 years of age.

What is the Treatment of Well-Differentiated Thyroid Cancer?

The primary therapy for well differentiated thyroid cancer is surgical removal of the tumor, which also allows preliminary staging of the disease. When a skilled thyroid surgeon is available, a bilateral near total removal of the thyroid (thyroidectomy) should be performed for most patients with known papillary or follicular carcinoma. However, there are many patients, previously treated with removal of half of the thyroid gland (hemithyroidectomy) who continue to thrive without disease recurrence. A particular dilemma occurs when the diagnosis of a minimally invasive follicular carcinoma is made after final pathology review, usually days after surgery is completed. Preliminary pathological analysis (frozen section) generally cannot distinguish benign from malignant follicular tumors at the time of surgery. Therefore removal of only half of the thyroid is generally performed. When the final diagnosis is minimally invasive follicular carcinoma options include: additional surgery to remove the remaining half of the thyroid gland (completion thyroidectomy), radioactive iodine destruction (ablation) of the remaining half of the thyroid) or thyroid hormone therapy alone, if the diagnosis is made by capsular invasion alone. The advantages of each approach are still debated.

When thyroid cancer extensively invades local neck structures, aggressive surgery, including removal of part of the trachea (air passageway) or esophagus (food passageway) should be considered. These patients require radioactive iodine therapy and often external beam radiation as well.

It may trouble some patients to realize that there are no absolute rules for the management of these cancers. Although the general characteristics of tumor behavior are understood, in any particular patient the choice of treatment is best made by physicians skilled in the management of patients with thyroid cancer.

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Radioiodine Therapy

Once papillary or follicular cancer has spread through the blood stream into the surrounding tissues or to distant sites (especially lungs and bones), the usual therapy is to administer a radioactive form of iodine (131I) to try to destroy the tumor. To understand this treatment, it is important to know the relationship between iodine and the thyroid gland.

The thyroid gland normally concentrates iodine from the bloodstream, and this process is stimulated by TSH (thyroid stimulating hormone) from the pituitary gland. The iodine is subsequently used to produce thyroid hormone (thyroxine, T4). Thyroid cancers or metastases from thyroid cancer concentrate only tiny amounts of iodine (or radioactive iodine) under normal conditions. However, when stimulated by high concentrations of TSH, papillary and follicular carcinoma and their metastases may be stimulated to concentrate significant amounts of iodine. This permits the delivery of a large radiation dose directly to the cancer, without damage to surrounding tissues. However, when the normal thyroid gland is present and producing normal amounts of thyroid hormone, the production of TSH by the pituitary remains relatively low. But if the entire thyroid gland is removed or destroyed, and the level of thyroid hormone is allowed to fall, the pituitary gland will increase TSH secretion dramatically. In turn, this will stimulate the thyroid cancer to concentrate radioactive iodine. To prepare for radioactive iodine therapy, patients must be off their thyroid hormone. We generally change patients from levothyroxine (Levothroid, Levoxyl, Synthroid, Unithroid and others) (T4) to Cytomel (T3) for four weeks and then discontinue the Cytomel for two weeks prior to administering the scanning dose of radioiodine. Patients are generally asked to adhere to a low iodine diet for several weeks prior to such therapy.

For radioactive iodine therapy to successfully treat metastatic thyroid cancer serum TSH must be elevated, which generally requires removal or destruction of the entire thyroid gland. Once that has been accomplished patients with residual tumor in the neck or known distant metastases are scanned after receiving a small amount (scanning dose) of radioactive iodine (131I, 2-10 millicuries or 123I, 1-2 millicuries), assuming the serum TSH concentration is greater than 25 uU/ml.

Patients then receive a therapeutic dose of 131I, usually 150 millicuries or more in an attempt to destroy the tumor, provided a significant amount of iodine is concentrated in the areas of the cancer. A repeat scan is often performed after the therapeutic dose; post-therapy scans identify additional sites of disease in approximately ten percent of patients.

In most states, treatment with large doses of radioactive iodine requires a one to several day hospitalization, until the amount of radioactivity in the body falls to levels which will not be hazardous to other people. However, this treatment has proved to be safe and well-tolerated, and may be curative in patients with well-differentiated thyroid cancer even after the tumor has spread to the lungs. The treatment is generally well tolerated, however, nausea, vomiting and pain in the salivary glands may occur. Salivary gland damage after this treatment may leave patients with a dry mouth.

Because of the safety and effectiveness of radioactive iodine in patients with more aggressive thyroid cancer, many physicians also use it routinely in patients with less aggressive papillary and follicular cancers. In this situation, radioactive iodine is used to destroy tiny remnants of thyroid tissue still present after surgery. This may improve the prognosis and makes it easier to monitor patients for tumor recurrence using a blood test for thyroglobulin (see below). Whether radioactive iodine ablation improves the survival or recurrence rates in patients with favorable papillary carcinoma of the thyroid gland is still debated.

When surgery and radioactive iodine cannot check the growth of well-differentiated thyroid cancer, external radiation therapy to local tumor sites is often helpful. We continue to search for specific therapies when the tumor has spread widely and continues to grow. Current chemotherapy is rarely effective in this situation. Because lung metastases are often asymptomatic for years, when radioiodine is no longer effective, cautious observation is often recommended.

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How are Thyroid Cancer Patients Followed?

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. These follow-up visits should include a careful history and physical examination with particular attention to the neck area.

Periodic measurement of the blood level of the protein thyroglobulin is also important.

This substance is produced and released by normal thyroid cells and also by well-differentiated thyroid cancer cells. The blood level of thyroglobulin is very low after total thyroid gland removal, and in most patients who are taking thyroid hormone after thyroid surgery. An elevated or rising level of thyroglobulin is a "tumor marker" which generally implies persistent or growing thyroid cancer, but does not necessarily imply a poor prognosis. A high thyroglobulin level found in a follow-up examination alerts the physician to the possibility that other tests may be needed to be sure the tumor is not recurring. Approximately 20 to 30% of thyroid cancer patients have interfering antibodies in their blood which prevent accurate thyroglobulin measurement. Thyroglobulin production is stimulated by TSH; the blood thyroglobulin concentration rises when TSH increases. Therefore a low serum thyroglobulin at the time of an elevated TSH is particularly reassuring.

How often should imaging and scanning be done? Many different protocols have been suggested to follow patients with well-differentiated thyroid cancer. I generally modify the testing based on the tumor stage. Patients with favorable papillary carcinomas with undetectable serum thyroglobulin concentrations need the fewest imaging tests. After radioactive iodine ablation of residual thyroid tissue, many endocrinologists and patients want the reassurance of a subsequent negative scan. Fortunately, a new method of radioiodine scanning is available for select patients, which does not require withdrawal of thyroid hormone. Patients receive injections of human TSH (made by genetic engineering) known as Thyrogen (recombinant human TSH, rhTSH) to raise their TSH concentrations. Radioiodine scanning and thyroglobulin measurements are performed. A negative post-Thyrogen scan and a serum thyroglobulin concentration less than 2 ng/ml after Thyrogen injections is very reassuring. I generally restrict this scanning approach to patients who are expected to have a negative scan and who have a low serum thyroglobulin while on thyroid hormone therapy. In exceptional circumstances, radioactive iodine therapy can be performed after Thyrogen injections rather than after withdrawal of thyroid hormone.

Patients with persistent cancer need periodic rescanning and treatment with radioactive iodine. Currently, this is best done after withdrawing thyroid hormone. In some patients the radioiodine scan is negative but serum thyroglobulin is still high. Several approaches have been suggested. I generally start with a thyroid ultrasound. If abnormal tissue or lymph nodes are found, additional surgery is generally indicated, sometimes after an ultrasound guided biopsy. If the ultrasound is negative, administration of larger doses of radioiodine with subsequent scanning may help localize the sites of disease. If these tests are negative, other scans and/or x-rays are necessary to localize the disease sites. These may include but are not limited to PET scanning, chest x-ray, CT or MRI, head CT or MRI, bone survey, CT or MRI of the spine, sestimibi, thallium or octreotide scanning. Whether serial neck ultrasounds should be performed in all patients with well-differentiated thyroid carcinoma is an unanswered question. However, I recommend ultrasound in all patients with a history of locally invasive papillary thyroid carcinoma and in those with positive thyroglobulin antibodies where that tumor marker cannot be followed. You should feel comfortable asking the physician who is treating your tumor to discuss his or her choice of tests and treatments for your situation.

What about Thyroid Hormone Treatment?

If the thyroid gland has been mostly or completely removed, thyroid hormone must be taken for the body to remain normal (euthyroid). Even if part of the thyroid remains, levothyroxine (Levothroid, Levoxyl, Synthroid, Unithroid and others) (T4) administration is an important therapy which lowers blood TSH concentration and seems to prevent tumor recurrence. Thyroid hormone should be administered in sufficient quantities to suppress TSH levels to subnormal values, except when medically contraindicated. Sensitive TSH measurements are necessary for monitoring TSH concentrations to confirm that the serum TSH is below normal or at the lower limits of normal in patients at low risk of cancer recurrence. Patients with more aggressive forms of papillary or follicular cancer should take larger doses of thyroxine in order to suppress TSH to undetectable levels.

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