Thyroid  Cancers

Thyroid cancer is the most common endocrine cancer. An estimated 18,100 new cases of thyroid cancer will be diagnosed in the year 2000. The number of deaths from thyroid cancer projected for the year 2000 is 1,200, or 7% of all new thyroid cancer cases. Between 1973 and 1990, the incidence of thyroid cancer increased by 21%, whereas mortality from this cancer decreased by 23%.

The prevalence rate for occult thyroid cancers found at autopsy is 5%-10%, except in Japan and Hawaii, where the rate can be as high as 28%. Autopsy rates do not correlate with clinical incidence.

The incidence of thyroid nodules in the general population is 4%-6%, with nodules being more common in females than males. The prevalence of thyroid cancer in a solitary nodule or in multinodular thyroid glands is 10%-20%; this increases with irradiation of the neck (see “Etiology and risk factors” below).

Tumor types

Thyroid cancer is classified into four main types according to their morphology and biological behavior: papillary, follicular, medullary, and anaplastic. Differentiated (papillary and follicular) thyroid cancers account for > 90% of thyroid malignancies and constitute approximately 0.8% of all human malignancies. Medullary thyroid cancers represent 5%-10% of all thyroid neoplasms. About 80% of patients with medullary cancer have a sporadic form of the disease, while the remaining 20% have inherited disease. Anaplastic carcinoma represents £ 5% of all thyroid carcinomas.

Papillary thyroid carcinoma is the most common subtype and has an excellent prognosis. Most papillary carcinomas contain varying amounts of follicular tissue. When the predominant histology is papillary, the tumor is considered to be a papillary carcinoma. Because the mixed papillary-follicular variant tends to behave like a pure papillary cancer, it is treated in the same manner and has a similar prognosis.

Papillary tumors arise from thyroid follicular cells, are unilateral in most cases, and are often multifocal within a single thyroid lobe. They vary in size from microscopic to large cancers that may invade the thyroid capsule and infiltrate into contiguous structures. Papillary tumors tend to invade the lymphatics, but vascular invasion (and hematogenous spread) is uncommon.

Up to 40% of adults with papillary thyroid cancer may present with regional lymph node metastases, usually ipsilateral. Distant metastases occur, in decreasing order of frequency, in the lungs, bones, and other soft tissues. Older patients have a higher risk for locally invasive tumors and for distant metastases. Children may present with a solitary thyroid nodule, but cervical node involvement is more common in this age group; up to 10% of children and adolescents may have lung involvement at the time of diagnosis.

Follicular thyroid carcinoma is less common than papillary thyroid cancer, occurs in older age groups, and has a slightly worse prognosis. Follicular thyroid cancer can metastasize to the lungs and bones, often retaining the ability to accumulate radioactive iodine (which can be used for therapy).

Follicular tumors, although frequently encapsulated, commonly exhibit microscopic vascular and capsular invasion. Microscopically, the nuclei tend to be large and have atypical mitotic figures. There is usually no lymph node involvement.

Follicular carcinoma can be difficult to distinguish from its benign counterpart, follicular adenoma. This distinction is based on the presence or absence of capsular or vascular invasion, which can be evaluated after surgical excision but not by fine-needle aspiration (FNA).

Thyroglobulin, normally synthesized in the follicular epithelium of the thyroid, is present in well-differentiated papillary and follicular carcinomas and infrequently in anaplastic carcinomas but not in medullary carcinomas. Therefore, thyroglobulin immunoreactivity is considered to be indicative of follicular epithelial origin.

Hürthle cell carcinoma Hürthle cell, or oxyphil cell, carcinoma is a variant of follicular carcinoma. Hürthle cell carcinoma is composed of sheets of Hürthle cells and has the same criteria for malignancy as does follicular carcinoma. Hürthle cell carcinoma is thought to have a worse outcome than follicular carcinoma and is less apt to concentrate radioactive iodine.

Medullary thyroid carcinoma originates from the C-cells (parafollicular cells) of the thyroid and secretes calcitonin. On gross examination, most tumors are firm, grayish, and gritty.

Sporadic medullary thyroid carcinoma usually presents as a solitary thyroid mass; metastases to cervical and mediastinal lymph nodes are found in half of patients and may be present at the time of initial presentation. Distant metastases to the lungs, liver, bones, and adrenal glands most commonly occur late in the course of the disease. Secretory diarrhea, related to calcitonin secretion, can be a clinical feature of advanced medullary thyroid carcinoma.

Familial medullary thyroid carcinoma presents as a bilateral, multifocal process. Histologically, familial medullary carcinoma of the thyroid does not differ from the sporadic form. However, the familial form is frequently multifocal, and it is common to find areas of C-cell hyperplasia in areas distant from the primary carcinoma. Another characteristic feature of familial medullary carcinoma is the presence of amyloid deposits.

Anaplastic carcinoma Anaplastic tumors are high-grade neoplasms characterized histologically by a high mitotic rate and lymphovascular invasion. Aggressive invasion of local structures is common, as are lymph node metastases. Distant metastases tend to occur in patients who do not succumb early to regional disease. Occasional cases of anaplastic carcinoma have been shown to arise from preexisting differentiated thyroid carcinoma or in a preexisting goiter.

Other tumor types Lymphomas of the thyroid account for < 5% of primary thyroid carcinomas. Other tumor types, such as teratomas, squamous cell carcinomas, and sarcomas, may also rarely cause primary thyroid cancers.

Epidemiology

Age and gender Most patients are between the ages of 25 and 65 years at the time of diagnosis of thyroid carcinoma. Women are affected more often than men (2:1 ratio for the development of both naturally occurring and radiation-induced thyroid cancer).

Etiology and risk factors

Differentiated thyroid cancer

Therapeutic irradiation External low-dose radiation therapy to the head and neck during infancy and childhood, frequently used between the 1940s and ’60s for the treatment of a variety of benign diseases, has been shown to predispose an individual to thyroid cancer. The younger a patient was at the time of radiation exposure, the higher is the subsequent risk of developing thyroid carcinoma. Also, as mentioned above, women are at increased risk of radiation-induced thyroid cancer. There is approximately a 25- to 30-year mean latency period from the time of low-dose irradiation to the development of thyroid cancer.

As little as 11 cGy and as much as 2,000 cGy of external radiation to the head and neck have been associated with a number of benign and malignant diseases. It was once felt that high-dose irradiation (> 2,000 cGy) to the head and neck did not increase the risk of neoplasia. However, recently it has been shown that patients treated with mantle-field irradiation for Hodgkin’s disease are at increased risk of developing thyroid carcinoma, compared with the general population, although they are more likely to develop hypothyroidism than thyroid cancer.

Radiation-associated thyroid cancer has an identical natural history and prognosis as sporadic thyroid cancer.

Other factors Besides radiation-induced thyroid cancer, there are only sparse data on the etiology of differentiated thyroid cancer.

Medullary thyroid cancer

Genetic factors In addition to sporadic medullary thyroid cancer, which represents the majority of cases, there are three hereditary forms: familial medullary thyroid carcinoma; multiple endocrine neoplasia type 2A (MEN 2A), characterized by medullary thyroid cancer, pheochromocytomas, and hyperparathyroidism; and multiple endocrine neoplasia type 2B (MEN-2B), characterized by medullary thyroid cancer, marfanoid habitus, pheochromocytomas, and neuromas. These syndromes are associated with germ-line mutations of the RET proto-oncogene, which codes for a receptor-like tyrosine kinase. Familial medullary thyroid carcinoma is inherited as an autosomal dominant trait with high penetrance and variable expression. (For a discussion of genetic testing to screen for RET mutations in MEN-2A kindreds, see “Screening and diagnosis” below.)

Signs and symptoms

Most thyroid cancers present as asymptomatic thyroid nodules. Patients may feel pressure symptoms from nodules as they begin to increase in size. A change in the voice can be caused by a thyroid cancer or benign goiter. The voice change usually occurs when there is compression of the larynx or invasion of the recurrent laryngeal nerve.

On physical examination, a thyroid nodule that is hard or firm and fixed may represent a cancer. The presence of palpable enlarged nodes in the lateral neck, even in the absence of a palpable nodule in the thyroid gland, could represent metastases to the lymph nodes.

Screening and diagnosis

As mentioned above, thyroid nodules are present in 4%-6% of the general population and in a higher percentage of individuals who have had irradiation to the head and neck region. Most thyroid nodules are benign (colloid nodules or adenomas); therefore, it is important for the work-up to lead to surgical resection for malignant nodules and avoid unnecessary surgery for benign lesions. Although most solid nodules are benign, thyroid carcinomas usually present as solid nodules. A cystic nodule or a “mixed” (cystic-solid) lesion is less likely to represent a carcinoma and more likely to be a degenerated colloid nodule.

History The history is very important in the evaluation of thyroid nodules. If there is a history of irradiation to the head and neck, the risk of there being a cancer in the nodule is higher (as great as 50%, as compared with a 10%-20% risk in nonirradiated patients).

Age also is important in the evaluation of thyroid nodules. Nodules that occur in either the very young or the very old are more likely to be cancerous, particularly in men.

A new nodule or a nodule that suddenly begins to grow is worrisome as well.

FNA should be the initial diagnostic test for the evaluation of thyroid nodules. First, FNA can determine whether the lesion is cystic or solid. For solid lesions, cytology can yield one of three results: (1) benign, (2) malignant or suspicious, and (3) indeterminate. The accuracy of cytologic diagnosis from FNA is 70%-80%, depending on the experience of the person performing the aspiration and the pathologist interpreting the cytologic specimen.

Imaging modalities Ultrasound and radionuclide (radioiodine and technetium) scans are also used in the evaluation of thyroid nodules.

Ultrasound can be used to determine whether a nodule is cystic or solid. Ultrasound cannot differentiate a benign solid nodule from a malignant one, but it can be used to assess the number of nodules present and their size. A nodule in a gland with multiple other nodules of similar size is unlikely to be malignant. A dominant nodule in a multinodular gland carries a risk of malignancy similar to that of a true solitary nodule.

Thyroid isotope scans cannot differentiate absolutely a benign from a malignant nodule, but can, based on the functional status of the nodule, assign a probability of malignancy. “Hot” thyroid nodules (ie, those that concentrate radioiodine) represent functioning nodules, whereas “cold” nodules are nonfunctioning lesions that do not concentrate the isotope. Most thyroid carcinomas occur in cold nodules, but only 10% of cold nodules are carcinomas. It is not necessary to operate on all cold thyroid nodules.

Calcitonin level Medullary thyroid carcinomas usually secrete calcitonin, which is a specific product of the thyroid C-cells (parafollicular cells). In patients who have clinically palpable medullary carcinoma, the basal calcitonin level is almost always elevated. In patients with smaller tumors or C-cell hyperplasia, the basal calcitonin level may be normal, but administration of synthetic gastrin (pentagastrin) and calcium results in marked elevation of calcitonin. The use of calcitonin levels as a tumor marker and stimulation screening in familial forms of medullary cancers has been largely replaced by genetic testing (see below).

Carcinoembryonic antigen (CEA) Serum CEA is also elevated in patients with medullary thyroid cancer.

Ruling out pheochromocytoma Medullary thyroid carcinoma can be associated with MEN-2A, MEN-2B, or familial non-MEN. Both the MEN-2A and MEN-2B syndromes are characterized by medullary thyroid cancer and pheochromocytoma. Thus, in any patient with familial medullary thyroid carcinoma, it is imperative that the preoperative work-up include a determination of 24-hour urinary catecholamines (metanephrine and vanillylmandelic acid) to rule out the presence of a pheochromocytoma.

Genetic testing Germ-line mutations in the RET proto-oncogene are responsible for familial non-MEN medullary thyroid carcinoma in addition to MEN-2A and MEN-2B. DNA analysis performed on a peripheral blood sample is a highly reliable method for identifying the presence of a RET mutation.

Because all persons who inherit the mutation develop medullary thyroid carcinoma, total thyroidectomy is recommended for all such affected individuals. This should be performed by age 5 or 6 years for carriers of the mutations for familial non-MEN medullary thyroid carcinoma and MEN-2A. Those with the mutation for MEN-2B should undergo total thyroidectomy during infancy because of the very early onset of aggressive medullary thyroid carcinoma in that syndrome.

Periodic determinations of stimulated calcitonin levels may help make the early diagnosis of medullary thyroid carcinoma in those who do not undergo surgery but will not always prevent the development of metastatic medullary thyroid carcinoma.

Staging and prognosis

Unlike most other cancers, in which staging is based on the anatomic extent of disease, the International Union Against Cancer (UICC) staging of thyroid cancer also takes into consideration patient age at the time of diagnosis and tumor histology.

Differentiated thyroid cancers Recurrence and death following initial treatment of differentiated thyroid cancer can be predicted using a number of risk classification schemes. The most commonly used systems are the AMES (age, metastases, extent, and size) and AGES (age, grade, extent, and size) classifications.

Low-risk patients are generally those < 45 years of age with low-grade nonmetastatic tumors that are confined to the thyroid gland and are < 1-5 cm in size. Low-risk patients enjoy a 20-year survival rate of 97%-100% after surgery alone.

High-risk patients are those > 45 years old with a high-grade, metastatic, locally invasive tumor in the neck or with a large tumor. Large size is defined by some authors as > 1 cm and by other authors as > 2 or > 5 cm. The 20-year survival rate in the high risk group drops to between 54% and 57%.

Intermediate-risk patients include young patients with a high-risk tumor (metastatic, large, locally invasive, or high grade), or older patients with a low-risk tumor. The 20-year survival rate in this group of patients is ~ 85%.

Medullary thyroid carcinoma has an overall 10-year survival rate of 40%-60%. When medullary carcinoma is discovered prior to becoming palpable, the prognosis is much better: Patients with stage I medullary tumors (ie, tumors < 1 cm or nonpalpable lesions detected by screening and provocative testing) have a 10-year survival rate of 95%.

Stage II medullary cancers (tumors > 1 cm but < 4 cm in size) are associated with survival rate of 50%-90% at 10 years. Patients who have lymph node involvement (stage III disease) have a 10-year survival rate of 15%-50%.

When there are distant metastases (stage IV), the long-term survival rate is < 15%. In patients with metastatic medullary thyroid cancer, the disease often progresses at a very slow rate, and patients may remain alive with disease for many years.

Anaplastic thyroid cancer does not have a generally accepted staging system, and all patients are classified as having stage IV disease. Anaplastic carcinoma is highly malignant and has a poor 5-year survival rate (0%-25%). Most patients die from uncontrolled local disease within several months of diagnosis.

Treatment

As most thyroid nodules are not malignant, it is important to differentiate malignant from benign lesions to determine which patients should undergo surgery  If the cytologic result from FNA indicates that the nodule is benign, which is the case most of the time, the nodule can be safely followed. The patient is placed on thyroxine therapy to suppress thyroid-stimulating hormone (TSH) and is reevaluated in 6 months. Adequate suppression is considered to be a TSH level of 0.2-0.4 m µ/mL for 6 months.

Surgery

Malignant or indeterminate cytologic features are the main indications for surgery.

Malignant nodule

Differentiated thyroid cancer If the cytologic result shows a malignant lesion, a thyroidectomy should be performed. There is significant debate in the literature regarding the extent of thyroid surgery for primary tumors confined to one lobe. The surgical options include a total lobectomy, total lobectomy with contralateral subtotal lobectomy (subtotal thyroidectomy), or total thyroidectomy. The decision about which operation to perform should be based on the risk of local recurrence and the anticipated use of radioactive iodine (see “Radioactive iodine-131” below).

Most authorities agree that a good-risk patient (age < 45 years) with a 1-cm or smaller papillary thyroid cancer should undergo ipsilateral total lobectomy alone. Most experts also agree that total thyroidectomy (or at least subtotal thyroidectomy) is appropriate for high-risk patients with high-risk tumors. Intermediate-risk patients are treated with total lobectomy alone or total (or subtotal) thyroidectomy plus postoperative radioactive iodine.

The necks of all patients should be palpated intraoperatively. If positive nodes are found, a regional lymph node dissection should be performed.

Medullary carcinoma Patients with medullary thyroid cancer should be treated with total thyroidectomy and a sampling of the regional nodes. If there is involvement of the nodes, a modified neck dissection should be performed (see “Lymph node dissection” below). If the cancer is confined to the thyroid gland, the patient is usually cured. Postoperative adjuvant external radiation may be used in certain circumstances (see “External radiation therapy” below).

Anaplastic carcinoma A tracheostomy often is required in patients with anaplastic thyroid cancer because of compression of the trachea. If the tumor is confined to the local area, a total thyroidectomy may be indicated to reduce local symptoms produced by the tumor mass. Radiation therapy is used to improve locoregional control, often together with radiosensitizing chemotherapy.

Indeterminate or suspicious nodule

The nodule that yields indeterminate or suspicious cytologic results and that is cold on thyroid scanning should be removed for histologic evaluation. The initial operation in most patients should be a total lobectomy, which entails removal of the suspicious nodule, hemithyroid, and isthmus. The specimen may then sent for frozen-section analysis during the operation. If the diagnosis is a colloid nodule, no further resection of the thyroid is required.

Follicular lesion If frozen-section biopsy results indicate a follicular lesion in a patient who is a candidate for total thyroidectomy, and a decision cannot be made as to whether the lesion is benign or malignant, two options are available: (1) stop and wait for final confirmation of the diagnosis, which may require a future operation; or (2) proceed with a subtotal or total thyroidectomy, which obviates the need for a later operation.

Hürthle cell carcinoma If the nodule is diagnosed as a Hürthle cell carcinoma, a total thyroidectomy is generally recommended for all large invasive lesions. Small lesions can be managed with total lobectomy However, controversy remains over the optimal treatment approach for this cancer.

Lymph node dissection

Therapeutic dissection Therapeutic central neck node dissection should be performed for medullary carcinomas and other thyroid neoplasms with nodal involvement. The dissection should include all of the lymphatic tissue in the pretracheal area and along the recurrent laryngeal nerve and anterior mediastinum. If there are clinically palpable nodes in the lateral neck, a modified neck dissection is performed.

Prophylactic dissection There is no evidence that performing prophylactic neck dissections improves survival. Therefore, aside from medullary thyroid cancer patients, who have a high incidence of involved nodes, only therapeutic neck dissection is indicated.

Removal of individual abnormal nodes (“berry picking”) is not advised when lateral neck nodes are palpable, because of the likelihood of missing involved nodes and disrupting involved lymphatic channels.

Metastatic or recurrent disease

Survival rates from the time of the discovery of metastases (lung and bone) from differentiated thyroid cancer are less favorable than survival rates associated with local recurrences (5-year survival rates of 38% and 50%, respectively). Survival also depends on whether the metastatic lesions take up I-131. Fortunately, most lesions take up radioactivity and can be treated with I-131.

Surgery, with or without I-131 ablation (discussed below), can be useful for controlling localized sites of recurrence. Approximately half of patients who undergo surgery for recurrent disease can be rendered free of disease with a second operation.

Radioactive I-131

Uses in papillary or follicular carcinoma

There are two basic uses for I-131 in patients diagnosed with papillary or follicular thyroid carcinoma: (1) the ablation of normal residual thyroid tissue after thyroid surgery, and (2) the treatment of thyroid cancer, either residual disease in the neck or metastasis to other sites in the body. It should be emphasized that patients with medullary, anaplastic, and most Hürthle cell cancers do not benefit from I-131 therapy.

Postoperative ablation of residual thyroid tissue should be considered in high-risk patients and patients with high-risk tumors. Ablation of residual normal thyroid tissue allows for the use of I-131 scans to monitor for future recurrence, possibly destroys microscopic foci of metastatic cancer within the remnant, and improves the accuracy of thyroglobulin monitoring.

Ablation must also be accomplished in patients with regional or metastatic disease prior to the use of I-131 for treatment, as the normal thyroid tissue will preferentially take up iodine compared to the cancer.

Following surgery, the patient should not be given thyroid hormone replacement. The TSH level should be determined approximately 4-6 weeks after surgery; in patients who underwent a total or subtotal thyroidectomy, TSH will generally be > 50 m µ/mL. A postoperative iodine scan can then be performed. If this scan documents residual thyroid tissue, an ablative dose of I-131 should be given. The patient should be advised not to undergo any radiographic studies with iodine during ablation therapy and to avoid seafood and vitamins or cough syrups containing iodine.

Iodine-131 dose In general, a dose of 75-100 mCi will ablate residual thyroid tissue within 6 months following ingestion. In some patients, it may take up to 1 year for complete ablation to occur. Patients should be monitored following ablation, and when they become hypothyroid, hormone replacement therapy should be given until they are clinically euthyroid and TSH is suppressed. TSH should be < 0.1 m µ/mL.

Follow-up I-131 scan Approximately 6 months after ablation of the thyroid remnant, a follow-up I-131 scan should be performed. Recombinant human thyrotropin (Thyrogen) is now available. Patients may continue on thyroid replacement and receive two doses of thyrotropin prior to I-131 scanning. The sensitivity of scanning under these conditions is lower than that in the hypothyroid state, but this approach can prevent the symptoms of hypothyroidism.

As an alternative, the patient may be withdrawn from levothyroxine (T₄) for a minimum of 4 weeks prior to the scan. The patient may be switched to liothyronine (T₃[Cytomel, Triostat]) for their first 2 weeks to decrease the period of hypothyroidism but must remain off T3 for a minimum of 2 weeks prior to I-131 scanning. The TSH level at this time should be > 50 U/mL to confirm adequate thyroid ablation.

In general, a dose of 2-5 mCi of I-131 is given and the patient is scanned 48 hours later. If there is any abnormal uptake of I-131, the patient is presumed to have residual thyroid cancer and should be treated.

Recombinant TSH (Thyrogen) is now available and can replace thyroxine withdrawal in selected patients.

Treatment of residual cancer For disease in the tumor bed or lymph nodes, an I-131 dose of 150 mCi is given. For disease in the lungs or bone, the I-131 dose is 200 mCi. Following this therapy, the patient is again put on thyroid hormone replacement and adequate suppression is maintained by monitoring TSH levels.

Follow-up Some clinicians advocate obtaining a repeat scan in 1 year, along with a chest x-ray, and repeating this procedure until a negative scan is obtained. However, the frequency of repeat scans and the dose of I-131 are rather controversial, and should be guided by the individual’s risk profile.

Following thyroid remnant ablation, serum thyroglobulin measurements are useful in monitoring for recurrence. Since thyroglobulin measurements in a patient receiving thyroid hormone replacement may be suppressed, a negative test may be incorrect ~ 10% of the time. In general, the presence of disease is accurately predicted by a thyroglobulin value > 5 ng/mL while the patient is in the suppressed state and by a value > 10 ng/mL in the hypothyroid state.

Chest x-rays should continue to be done at yearly intervals for at least 10 years. Neck ultrasound is also very useful to evaluate locoregional recurrence. Continued monitoring is necessary as late recurrence can occur. It should be pointed out that certain aggressive tumors may neither be radioactive iodine–avid nor synthesize thyroglobulin.

Side effects and complications of I-131

Acute effects The acute side effects of I-131 therapy include painful swelling of the salivary glands and nausea. Ibuprofen or other pain relievers are usually used to decrease salivary gland discomfort. Nausea may be treated with standard antiemetics.

Rarely, in patients with significant residual thyroid tissue, radioactive iodine may cause acute thyroiditis due to a rapid release of thyroid hormone. This can be treated with steroids and b-blockers.

Patients must also be cautioned not to wear contact lenses for at least 3 weeks following ingestion of I-131, as the tears are radioactive and will contaminate the lenses and possibly lead to corneal ulceration.

Bone marrow suppression and leukemia are potential long-term complications of I-131 therapy but are poorly documented and appear to be extremely rare. Patients should have a CBC performed prior to ingestion of an I-131 dose to ensure adequate bone marrow reserve. They should also have yearly blood counts. Leukemia occurs rarely with doses < 1,000 mCi.

Pulmonary fibrosis may be seen in patients with pulmonary metastases from papillary or follicular thyroid cancer who are treated with I-131. Those with a miliary or micronodular pattern are at greater risk, as a portion of normal lung around each lesion may receive radiation, leading to diffuse fibrosis.

Effects on fertility Recent data have documented an increase in follicle-stimulating hormone (FSH) levels in one-third of male patients treated with I-131. Changes in FSH after one or two doses of I-131 are generally transitory, but repeated doses may lead to lasting damage to the germinal epithelium.

The effects of I-131 on female fertility have been investigated. A recently published article showed no significant difference in the fertility rate in women receiving radioactive iodine.

No ill effects have been noted in the offspring of treated patients.

External radiation therapy

Papillary or follicular thyroid cancer

There are a number of indications for external radiation in the treatment of papillary or follicular thyroid carcinoma. Surgery followed by radioactive iodine may be used for disease that extends beyond the capsule. However, if all gross disease cannot be resected, or if residual disease is not radioactive iodine–avid, external radiation is used as part of the initial approach for locally advanced disease.

Unresectable disease External radiation is useful for unresectable disease extending into the connective tissue, trachea, esophagus, great vessels, and anterior mediastinum. For unresected disease, doses of 6,000-6,500 cGy are recommended. The patient should then undergo I-131 scanning and, if uptake is detected, a dose of I-131 should be administered.

Recurrence after resection External radiation may also be used after resection of a recurrent papillary or follicular carcinoma that no longer shows uptake of I-131. In this situation, doses of 5,000-6,000 cGy are delivered to the tumor bed to prevent local recurrence. Multiple-field techniques and extensive treatment planning are necessary in order to deliver high doses to the target volume without the risk of significant complications.

Palliation of bone metastases External radiation therapy is useful in relieving pain from bone metastasis. If the metastasis shows evidence of I-131 uptake, the patient should be given a therapeutic dose of I-131 followed by local external radiation therapy to the lesion of up to 4,000-5,000 cGy.

Anaplastic thyroid carcinoma

Anaplastic carcinoma of the thyroid is an exceptionally aggressive disease. It often presents as a rapidly expanding mass in the neck and may not be completely resected. External radiation to full dose (6,000-6,500 cGy) may slow the progress of this disease but rarely controls it.

Chemoradiation There are reports of the use of accelerated fractionation regimens of external radiation (160 cGy twice daily to 5,700 cGy) with weekly doxorubicin in patients with anaplastic thyroid cancer, as well as reports of the combination of doxorubicin and cisplatin (Platinol) with external radiation. These regimens have improved local control but at the expense of increased toxicity. Unfortunately, the majority of patients die of progressive disease.

Medullary thyroid carcinoma

External radiation has been used for medullary thyroid cancer in the postoperative setting. Indications include positive surgical margins, gross residual disease, or extensive lymph node metastasis. The recommended dose is 5,000 cGy in 5 weeks.

Role of Medical therapy

Differentiated thyroid cancer

Thyroid hormone replacement As mentioned above, thyroid hormone replacement is used to suppress TSH in most patients with differentiated thyroid cancer after surgery, prior to I-131 scanning and (as appropriate) treatment.

Systemic chemotherapy is used for widespread disease, although regimens have not been very effective to date.

Medullary thyroid carcinoma

In medullary thyroid carcinoma, the usual treatment is surgical. In patients with familial medullary carcinoma who have a coexisting pheochromocytoma, appropriate control of catecholamine hypersecretion should precede thyroid surgery.

Anaplastic thyroid carcinoma

As mentioned above, the usual treatment for anaplastic thyroid cancer is surgery. Like radiotherapy, chemotherapy is an important alternative approach, but further evaluation is needed to optimize its effectiveness.